EFFECT OF UPPER-EXTREMITY REHABILITATION ON EFFORT REQUIRED TO USE THE MORE AFFECTED ARM AFTER ACQUIRED BRAIN INJURY BRAD HARRIS SOKAL

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1 EFFECT OF UPPER-EXTREMITY REHABILITATION ON EFFORT REQUIRED TO USE THE MORE AFFECTED ARM AFTER ACQUIRED BRAIN INJURY by BRAD HARRIS SOKAL DISSERTATION COMMITTEE GITENDRA USWATTE, Ph.D., Chair VICTOR MARK, M.D. DAVID MORRIS, Ph.D. EDWARD TAUB, Ph.D. REX WRIGHT, Ph.D. A DISSERTATION Submitted to the graduate faculty of The University of Alabama at Birmingham, in partial fulfillment of the requirements for the degree of Doctor of Philosophy BIRMINGHAM, ALABAMA 2014

2 Copyright by Brad Harris Sokal 2014 ii

3 ABSTRACT OF DISSERTATION GRADUATE SCHOOL, UNIVERSITY OF ALABAMA AT BIRMINGHAM Degree Ph.D. Program Clinical Medical Psychology, Department of Psychology Name of Candidate Brad Sokal Committee Chair Gitendra Uswatte, Ph.D. Title Effect of Upper-Extremity Rehabilitation on Effort Required to Use the More Affected Arm after Acquired Brain Injury Constraint-Induced Movement therapy, or CI therapy, is one of the few techniques that controlled, randomized studies show to substantially reduce the incapacitating motor deficit of the more-affected upper-extremity of patients with mild to moderately severe hemiparesis. The therapy for individuals with mild to moderate motor impairment of their more-affected arm involves a) training of more-affected arm for 3.5 hours per day for 10 consecutive weekdays, b) following shaping principles when conducting the training, c) restraining the less-affected arm for a target of 90% of waking hours, and d) administering a package of behavioral techniques designed to transfer gains to daily life. Imaging techniques for studying structural neuroplastic changes after CI therapy show substantial increases in contralateral primary sensorimotor cortex and motor areas anterior to these loci, equivalent changes in the ipsilateral cortex, and the hippocampus after CI therapy. It is thought that one mechanism responsible for the large gains in everyday use of the more-affected arm may be that the increase in central nervous system (CNS) representation makes movement of the more-affected arm less effortful and less demanding of attention. iii

4 The effect of CI therapy on effort required to move the more-affected arm during an upper-extremity motor task was examined in two studies in patients with mild-tomoderate upper-extremity hemiparesis. Effort was measured by systolic blood pressure (SBP), heart rate (HR), and the Category Ratio Scale (CR10). In the first study, chronic stroke patients (n = 21) received either a telerehabilitation form or CI therapy or standard CI therapy. In the second study, multiple sclerosis (MS) patients (n = 17) received standard CI therapy or Complementary Alternative Medicine treatments. Participants in both studies moved a peg from a starting hole to a target hole and back with their moreaffected arm for 60 s in for each of four increasing levels of task difficulty. In addition, attention required to move the more-affected arm was studied using a dual-attention task, i.e., upper-extremity pegboard and arithmetic tasks, performed simultaneously. In the first study with chronic stroke patients, participants in both CI therapy groups showed very large gains in the quality of movement of the more-affected arm use as measured by the MAL, F(1, 14) = 200.5, p <.0001, d' = 2.9. In the second study with MS patients, participants in the CI therapy group showed very large MAL gains, F(1, 8) = 151.6, p <.0001, d' = 4.6. However, participants that received CAM treatments (e.g. massage, yoga) showed substantially smaller gains, F (1, 7) = 7.5, p <.05, d' =.6. The effort data from both studies indicated that the two testing paradigms functioned as intended, i.e., the difficult task levels required more effort than the easy ones, and performance of the motor and cognitive tasks in the dual-task compared to single-task condition was more demanding. In both stroke patients and MS patients, all three of the indices of effort increased monotonically with task difficulty, p s <.05. Correlations among the three indices of effort, CR10, SBP, and HR responses, however, iv

5 did not behave as expected. Although SBP and CR10 values were correlated in stroke patients, r(16) =.66, p<.01, HR values were not significantly correlated with either of the two indices. In MS patients, none of the three indices were correlated with another. For stroke patients, the results indicated perceived effort to move the more-affected arm during the motor task decreased after CI therapy, F(4, 56) = 3.3, p<.02. There was also a reduction in attention required to perform the motor and arithmetic tasks together, F(1, 11) = 5.5, p =.04, and a concomitant decrease in perceived effort, F(1, 12) = 14.3, p =.003, for the dual-attention task, relative to the single-tasks, after CI therapy. There were no significant improvements in any of the measures of effort or attention after CI therapy in the MS patients. The stroke study findings warrant testing in a study with a more rigorous design and larger sample size. v

6 DEDICATION This work is dedicated to my wife Lauren Sokal with love. vi

7 ACKNOWLEDGEMENTS I would never have been able to finish my dissertation without the guidance of my committee members, help from friends, and support from my family and wife. I would like to express my deepest gratitude to my mentor, Dr. Gitendra Uswatte, for his wise guidance, insights, and generous support throughout my doctoral research training. Second, I am indebted to my research group of Eva Trinh, Michael Brewer, Ezekiel Byrom, Jessica Latten, Andrew Jones, Samantha Flippo, Staci McKay, and Joydip Barman for their help with running subjects, processing data, and hashing out designs and ideas. This research would not have been possible without their dedication and comradeship. Third, I am indebted to the members of my dissertation committee, Drs. Edward Taub, David Morris, Victor Mark, and Rex Wright, for their valued encouragement, input, and guidance. Fourth, I would also like to thank my parents and brother. They were always supporting me and encouraging me with their best wishes. Finally, I want to express my deepest thanks to my wife, Lauren Sokal. She was always there supporting me through the ups and downs of graduate education. vii

8 TABLE OF CONTENTS Page ABSTRACT... iii DEDICATION... vi ACKNOWLEDGMENTS... vii LIST OF TABLES...x LIST OF FIGURES... xii LIST OF ABBREVIATIONS... xiv CHAPTER I. INTRODUCTION...1 Constraint-Induced Movement Therapy and Patient Effort...1 Public Health Implications of the Study...3 Three Dimensions of Effort...3 Cardiovascular Indices of Effort...4 Motivational Intensity Theory as a Model for Effort...5 Effort, Attention, and Motor Tasks...11 Effort and Motor Rehabilitation...13 Specific Aims METHODS...18 Participants...18 Apparatus...21 Measures...21 Procedures...24 Data Reduction...27 Data Analysis Study viii

9 Results Study Results DISCUSSION...77 LIST OF REFERENCES...87 APPENDICES A MOTOR ACTIVITY LOG...99 B CATEGORY RATIO SCALE MODIFIED FOR EFFORT C RULES FOR PROCESSING CARDIOVASCULAR DATA D UAB CITRG CARDIOVASCULAR SAFETY GUIDELINES E TASK INSTRUCTIONS WITH INCENTIVES F INSTITUTIONAL REVIEW BOARD APPROVAL ix

10 LIST OF TABLES Tables Page 1 Gender, Race, Age at Entry and Neurologic Characteristics of Stroke Patients and Multiple Sclerosis Patients MAL and WMFT Scores in Stroke Patients in TeleAutoCITE or Standard CI Therapy Pearson Correlations at Pre-treatment for SBP, HR, and CR10 Responses with the MAL and WMFT Partial Pearson Correlations at Post-treatment for Systolic SBP, HR, and CR10 responses with the MAL and WMFT, using Pre-treatment Scores as Covariates.39 5 MAL and WMFT Scores in Stroke Patients in TeleAutoCITE or Standard CI Therapy Pearson Correlations at Pre-treatment for SBP, HR, and CR10 Responses with the MAL and WMFT Pearson Correlations at Pre-treatment Between Performance Cost of the Dualvs. Single-task Condition and the MAL and the WMFT Partial Pearson Correlations at Post-treatment for SBP, HR, and CR10 for the Dual-task Condition with MAL and WMFT, using Corresponding Pre-Treatment Scores as Covariates Pearson Correlations at Pre-treatment for SBP, HR, and CR10 Responses with Performance Cost Mean MAL and WMFT Scores for MS Patients in CI Therapy and CAM Treatment Groups Pearson Correlations at Pre-treatment of SBP, HR, and CR10 Responses with MAL and WMFT...56 x

11 12 Partial Pearson Correlations at Post-treatment of SBP, HR, and CR10 Responses with MAL and WMFT, using Pre-Treatment Scores as Covariates Partial Pearson Correlations at Post-treatment of SBP, HR, and CR10 Responses with MAL and WMFT, using Pre-Treatment Scores as Covariates, for MS Patients in CI Therapy Partial Pearson Correlations at Post-treatment of SBP, HR, and CR10 Responses with MAL and WMFT, using Pre-Treatment Scores as Covariates, for MS Patients in CAM Therapy Pearson Correlations at Pre-treatment Between Performance Cost of the Dual- Versus Single-task Condition and the MAL and the WMFT Partial Pearson Correlations at Post-Treatment Between Performance Cost of the Dual- versus Single-task Condition and MAL and WMFT, using Pre-Treatment Scores as Covariates Pearson Correlations at Pre-treatment of SBP, HR, and CR10 Responses to the Dual-task Condition with the MAL and WMFT Partial Pearson Correlations at Post-treatment for SBP, HR, and CR10 for the Dual-task Condition with MAL and WMFT, using Corresponding Pre-Treatment Scores as Covariates Pearson Correlations at Pre-treatment Among SBP, HR, and CR10 Responses with Performance Costs...76 xi

12 LIST OF FIGURES Figure Page 1 The three effort continua: perception, physiology and performance Effort-difficulty relation at two levels of potential motivation for a fixed task and individuals with low- and high-ability Performance resource function: Task A requires less attentional resources to achieve optimal performance at an equivalent level of performance to Task B Pegboard motor task with arrows indicating both directions of movement Relationship in stroke patients between task difficulty and effort Indices A. systolic blood pressure B. heart rate C. Category Ratio Scale Relationship in stroke patients at pre-treatment between perceived effort (Category Ratio Scale) and systolic blood pressure Relationship in stroke patients at pre- and post-treatment between task difficulty and effort indices A. systolic blood pressure B. heart rate C. Category Ratio Scale Relationship in stroke patients between pre- to post-treatment changes in heart rate and MAL Arm Use scores Relationship in stroke patients under single- and dual-task conditions between performance and testing occasion Relationship in stroke patients under single- and dual-task conditions between Category Ratio Scale and testing occasion Relationship in stroke patients between pre- to post-treatment changes in systolic blood pressure and A. MAL Arm Use scores B. WMFT Performance Rate Relationship in stroke patients at pre-treatment between systolic blood pressure and performance cost...51 xii

13 13 Relationship in multiple sclerosis patients at pre-treatment between task difficulty and effort indices A. systolic blood pressure B. heart rate C. Category Ratio Scale Relationship in MS patients between heart rate response and A. MAL Arm Use scores and B. WMFT Performance Rate Relationship in MS patients at pre- and post-treatment between task difficulty and effort indices A. systolic blood pressure B. heart rate C. Category Ratio Scale Relationship in MS patients in the CI therapy group between pre- to posttreatment changes in CR10 responses and MAL Arm Use scores Relationship in MS patients under single- and dual-task conditions between performance and testing occasion for A. CI therapy B. CAM treatments Relationship in MS patients under single- and dual-task conditions between Category Ratio Scale and testing occasion for A. CI Therapy B. CAM treatments Relationship in MS patients between pre- to post-treatment changes in systolic blood pressure and MAL Arm Use scores...75 xiii

14 LIST OF ABBREVIATIONS ANOVA BP CAM CI Therapy CNS CR10 CV DBP fmri HR LED MAL MS RPE SBP Tele-AutoCITE UAB WMFT Analysis of Variance Blood Pressure Complementary Alternative Medicine Constraint-Induced Movement Therapy Central Nervous System Category Ratio Scale Cardiovascular Diastolic Blood Pressure Functional Magnetic Resonance Imaging Heart Rate Light Emitting Diode Motor Activity Log Multiple Sclerosis Rating of Perceived Exertion Systolic Blood Pressure Tele-rehabilitation Automated Constraint-Induced Movement Therapy University of Alabama at Birmingham Wolf Motor Function Test xiv

15 1 Introduction Constraint-Induced Movement Therapy and Patient Effort Research on monkeys that had sensation surgically abolished from a forelimb has shown that such animals do not use their deafferented limb even though they regain sufficient motor ability to do so 2-6 months after surgery (Taub, 1977, 1980). The monkeys do not use their deafferented forelimb, because when the animals attempt to use that forelimb soon after surgery, they still do not have sufficient motor control to support their weight successfully or manipulate objects. These failed attempts punish use of the deafferented forelimb and suppress its use even after the monkeys recover sufficient motor control. Meanwhile, the tendency to use the intact forelimb and hind limbs is strengthened, because the monkeys are able to support their weight and manipulate objects successfully with such compensatory strategies. Learned nonuse of the deafferented limb, thereby, becomes permanent unless it is counterconditioned using some simple behavioral methods. One factor that could have contributed to learned nonuse of the deafferented limb, in addition to failed attempts to use that limb and successful attempt to use compensatory strategies, is that the increased effort required to use the deafferenated limb soon after surgery functions as punishment. Animal studies into increasing the physical effort required to emit a designated operant response (e.g., Mowrer & Jones, 1943; Skinner, 1938, 1950; Solomon, 1948) have suggested that increasing the effort required to obtain reinforcement is similar to adding an aversive consequence (i.e., punishment) for the response (e.g., Blough, 1966; Chung, 1965; Miller, 1968, 1970; Solomon, 1948).

16 2 Based on the aforementioned studies with monkeys, E. Taub and colleagues developed Constraint-Induced Movement therapy (CI therapy), which has been shown in randomized controlled studies to substantially reduce the incapacitating motor deficit of the more-affected arm of stroke survivors (Taub et. al, 1993; Taub & Uswatte, 2003; Taub et al., 2006; Wolf et. al, 2009). CI therapy for individuals with mild to moderate motor impairment of their more-affected arm involves a) training of more-affected arm use for 3.5 hours per day for 10 consecutive weekdays using functional tasks, b) following shaping principles when conducting the training c) restraining the less-affected arm both in the laboratory and at home over the treatment period for a target of 90% of waking hours, and d) administering a package of behavioral techniques (e.g., keeping a daily diary, negotiating behavioral contracts) designed to transfer gains from the treatment setting to daily life. Patients after CI therapy show very large gains in use of the more-affected arm in daily life, large gains in laboratory-based tests of more-affected arm motor ability, and improvement in their quality of life (Taub & Uswatte, 2006). Imaging techniques for studying structural neuroplastic changes after CI therapy show substantial contralateral primary sensorimotor cortex and motor areas anterior to these loci, equivalent changes in the ipsilateral cortex, and the hippocampus (Gauthier et al., 2008; Mark et al., 2014). It is thought that a mechanism responsible for the large gains in everyday use of the moreaffected arm (d = 3.2; Taub et al., 2006; Taub & Uswatte, 2006; Wolf et al., 2006) may be that the increase in the CNS representation makes movement of the more-affected arm less effortful and require less attention (Gauthier et al., 2008; Mark et al., 2014). The requirement of less effort to move the more-affected arm, in turn, makes its use more

17 3 rewarding, and, hence, increases the frequency with which that arm is used. Public Health Implications of the Study In the United States, the estimated prevalence of stroke and multiple sclerosis (MS) are 6,400,000 and 350,000, respectively (Rosati, 2001; NIH National Heart, Blood, and Lung Institute, 2006), and their estimated direct and indirect costs are greater than $80 billion (Whetten-Goldstein, Sloan, Goldstein, & Kulas, 1998; American Heart Association, 2010). There is a need to reduce the large economic, societal, and individual burden of these neurological conditions by improving the cost-effectiveness and efficacy of rehabilitation outcomes. Improving rehabilitation outcomes may help increase qualityadjusted life years (QALY) and reduce lost productivity. Upper-extremity hemiparesis, which is characterized by weakness and poor control of movement of the paretic arm, is a frequent and costly effect of stroke and a source of disability for MS (Cowan, Omerod, Rudge, 1990; Mark et. al, 2008; Winstein et al., 2004). Hemiparesis limits the ability of stroke survivors and individuals with MS to accomplish activities of daily living and degrades their quality of life (Nichols-Larsen, 2005). Three Dimensions of Effort Effort is conceptualized by Borg (1970) as the physical or mental energy required to achieve a task. Borg (1977), in addition, defines three dimensions, termed continua, along which to characterize effort: perceptual, performance, and physiological. Figure 1 illustrates these three effort continua. Borg considers the perceptual continuum to be fundamental because, in his view, an individual s perception of the effort being exerted underlies adaption to a situation (i.e., behavior). The performance continuum involves the behavioral response of an individual to the challenge at hand. The physiological

18 4 continuum consists of a number of variables, (e.g., cardiovascular measures, ventilation and respiration rates), to name just a few. The relationships among the three dimensions (perceptual, performance, and physiological) are not simple and linear with the result that it is difficult to measure effort, or energy expenditure, directly. Therefore, subjective and objective measures are used together to index effort. Figure 1. The three effort continua: perception, physiology and performance. S is the environmental situation, O is the organism, and R is the response in each of these continua. Adapted from Perceived Exertion and Pain Scales (p. 6) by G. Borg, 1998, Champaign, Illinois: Human Kinetics. Cardiovascular Indices of Effort Social psychologists and psychophysiologists have assembled substantial evidence that certain cardiovascular responses (i.e., changes relative to baseline) vary with effort. Common cardiovascular indices of effort in the modern literature include heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP). The link between effort and cardiovascular responsiveness was first proposed by Obrist (1976, 1981; see also Light, 1981) who argued that sympathetic nervous system influence on the heart and vasculature influence increases with task engagement. An increase in

19 5 sympathetic activity potentially produces simultaneous elevations in HR, SBP, and DBP (for further details, see Smith, Baldwin, & Christenson, 1990). Effort, in particular, appears to be reflected in responses mediated by sympathetic nervous system activity, including heart contractility, BP, and HR. However, heart contractility and SBP have been of special interest because (1) contractility is believed to be a relatively pure index of sympathetic influence (Berntson, Cacioppo, & Quigley, 1993) and (2) SBP is powerfully affected by the magnitude of heart contractions (SBP = contractility x vascular resistance). Systolic reactivity (elevations above baseline) should increase with effort unless (1) the induced sympathetic discharge yields a profound decrease in resistance in the blood vessel walls, or (2) sympathetic activity is exceptionally low (Papillo & Shapiro, 1990). Heart rate is also sensitive to effort but less so than SBP, because when engagement is modest, the sympathetic effect on heart rate is likely to be masked (e.g., Gendolla & Wright, 2005; Wright, 1998). Motivational Intensity Theory as a Model for Effort Brehm s motivational intensity theory (Brehm & Self, 1989; Brehm et al., 1983; Wright & Brehm, 1989) is concerned with the determinants of momentary effort. It draws from the classic difficulty law of motivation (Ach, 1935) and states that effort is determined by appraisals of task difficulty. In particular, it asserts that effort increases with task difficulty as long as success in the task is viewed as possible and worthwhile; when neither is viewed as the case, effort falls off sharply. There are several implications of Brehm s motivational intensity theory. First, engagement should be greatest when performance challenges are of moderate difficulty. Second, the relationship between engagement and difficulty of a challenge should be moderated by success importance.

20 6 Third, success importance should have no effect on effort when a challenge is deemed impossible. The above implications apply only to fixed challenges, which call for a particular level of performance (Brehm & Self, 1989). When a challenge is unfixed, which means there is no clear performance standard, effort should correspond to success importance until maximum, i.e., greatest possible, effort has been achieved. As shown in Figure 2, effort for a fixed task should increase with task difficulty and then drop precipitously for both low- and high-ability individuals (Wright, 1996). For low-ability individuals, the y-(effort) intercepts are higher than for high-ability individuals, because low-ability individuals perceive the task as more difficult. Inspection of the separate functions for low-ability and high-ability individuals reveals several implications about ability perception. First, low-ability individuals should strive harder on a task of fixed difficulty (i.e., greater effort and higher SBP values) than highability individuals as long as success is deemed possible and worthwhile. Second, lowability individuals should expend less effort than high-ability individuals when success is deemed impossible or excessively difficult, but worthwhile to high-ability individuals. Three, effort will be minimal irrespective of ability perception when the challenge is too great even for high-ability individuals. As an aside, increasing patient effort during physical rehabilitation with tasks of moderate difficulty is consistent with the behavioral techniques central to CI therapy for training of the more-affected arm in the laboratory, i.e., shaping, suggesting that tasks of moderate difficulty and maximum patient effort are factors in successful physical rehabilitation therapies.

21 Figure 2. Effort-difficulty relation at two levels of potential motivation for a fixed task and individuals with low- and high-ability. Adapted from The Psychology of Action: Linking Cognition and Motivation to Behavior (p. 431) by P. M. Gollwitzer and J. A. Bargh (Eds.), New York: Guilford. 7

22 8 Close to 100 studies have applied Brehm s intensity theory to the investigation of how effort varies with ability, value of the incentive for succeeding, and resource depletion. These studies have implications for the amount of effort individuals with upper-extremity impairment exert to use the more-affected arm and for factors that influence the effectiveness of physical rehabilitation. Typical studies supporting the basic intensity theory found that (a) when tasks are of moderate difficulty rather than mild or extreme difficulty, performance challenges elicit greater task engagement (e.g., Wright, Contrada, & Patene, 1986) and that (b) the relationship between task engagement and the difficulty of a possible challenge is moderated by perceived success importance (e.g., Wright, Williams, & Dill, 1992). These studies used SBP as the primary index of task engagement. As mentioned previously, difficulty appraisals are a function of both task difficulty and ability perceptions (Ford & Brehm, 1987; Kukla, 1972, 1974; Meyer, 1987; Smith & Pope, 1992). Extending the basic intensity theory to examine the effects of perceived ability on cardiovascular indices, Wright and Dill (1993) first manipulated the ability perceptions of subjects and then asked these subjects to perform a scanning task to earn a prize if a low or high performance standard was attained. When the performance standard was low, SBP reactivity tended to be greater for low perceived-ability than high perceived-ability subjects, F = 1.0, n.s., but when the standard was high, SBP reactivity was greater for high than low perceived-ability subjects, F(1,52) = 4.7, p <.05. Wright and colleagues (1994) expanded on this study by examining natural ability. They asked subjects to solve math problems described as easy, difficult, or extremely difficult. An ANOVA revealed an ability x task demand interaction, F(1, 104)

23 9 = 4.2, p =.05. High-ability subjects tended to evince greater anticipatory systolic reactivity the greater the challenge. By contrast, low-ability subjects manifested greater reactivity in the difficult condition than in the easy and extremely difficult conditions. Replicating and further extending these findings by a) experimentally inducing ability appraisals and (b) during performance, Wright and Dismukes (1995) found that HR tended to be greater for low than for high perceived-ability subjects when the standard was easy, F(l, 60) = 3.6, p<.06, but were greater for high- than for low ability subjects when the standard was difficult, F(l, 60) = 9.2, p <.003. To investigate the effect of incentive values on cardiovascular indices of effort, Eubanks, Wright, and Williams (2002) confronted participants with a cognitive challenge. Participants could earn a $100 prize or $10 prize by attaining a 90% success rate on computer memory tasks varying in difficulty from low to high. This study reported that HR data showed a difficulty x incentive value interaction, F(4, 360) = 2.4, p <.05. In particular, HR responses were proportional to task difficulty and unaffected by incentive value in all conditions except for the most difficult one. Where difficulty was greatest, $100 participants showed relatively high heart rate responsiveness, whereas $10 participants showed low HR responsiveness. These findings build on previous experiments (e.g., Brown, Smith, & Benjamin, 1998; Wright, Tunstall, Williams, Goodwin, & Harmon-Jones, 1995, Wright, Killebrew, & Pimpalapure, 2002) by providing evidence that CV responses are proportional to incentive value only under some task conditions. To examine the effect of energy depletion on cardiovascular indices of effort, Wright and colleagues (2003) asked subjects to perform an easy or hard counting task

24 10 (Task A) and then provided the chance to earn a modest incentive by attaining a low or high performance standard (Task B) for a mental arithmetic task. This study reported a significant Task A difficulty x Task B difficulty interaction for SBP data, F(1,67) = 10.1, p <.003, a performance period effect, F(1,68) = 4.2, p <.05, and a Task A difficulty x Performance Period interaction, F(1,68) = 55.6, p <.02. The finding of interest was that when Task A and B were both difficult, subjects had relatively weaker SBP responses (i.e., withdrew effort) to Task B. In contrast, subjects had relatively stronger SBP responses to Task B when Task A was easy. These SBP results partially replicated cardiovascular findings from a depletion study using a cognitive, as opposed to a motor, challenge (Wright & Penacerrada, 2002) and demonstrated that the cardiovascular influence of energy depletion depends on the difficulty of the challenge with which people are confronted. These studies on how effort varies with ability, value of the incentive for succeeding, and resource depletion have implications for (1) the amount of effort individuals with upper-extremity impairment will exert to use the more-affected arm and (2) for factors that influence the effectiveness of physical rehabilitation. First, as patients are of low-ability soon after acquired brain injury, use of their more-affected arm is effortful (i.e., aversive), making withdrawal of effort to use that arm likely. Second, as CI therapy increases the ability to use the more-affected arm, motor tasks, in turn, require less effort. Therefore, greater use of the more-affected arm to perform tasks in the free situation becomes likely. Third, because CI therapy uses shaping principles patients are encouraged continually to improve on their past performance, though by small increments. This, in turn, increases patient effort and positive reinforcement during the

25 11 rehabilitation process. In addition to CI therapy specifically, these implications apply to rehabilitation in general. For example, low-ability rehabilitation patients who are asked to perform extremely difficult motor tasks will tend to disengage from therapy. Another important implication is that incentives for rehabilitation patients to succeed with therapies will only optimize effort under some conditions, i.e., the incentives are of high importance. A third implication is that a series of difficult rehabilitation tasks may ultimately result in a withdrawing of patient effort. Effort, Attention, and Motor Tasks As mentioned previously, one mechanism hypothesized to account for the large gains in real-world more-affected arm use after CI therapy is reduction in effort and attention required to move the arm. Another explanation is that the involvement of the more-affected arm in activities of daily living becomes habitual rather than requiring less attention. Only one exploratory study provides empirical data on the relationship between the amount of effort exerted and attention required. Specifically, Bongard (1995) asked two groups of subjects to work on a primary mental arithmetic task and a secondary choice reaction time task simultaneously. One group of subjects could avoid an aversive tone by performing well on the mental arithmetic task, and the other group had no control over the tone. Subjects with control showed elevated cardiovascular responses and inferior secondary task performance than subjects without control. Bongard concluded that the increases in attentional demands positively correlate with effort expenditures. Although it is well-documented that tasks require less attention with practice or training (Bherer et al., 2005; Levy & Pashler, 2001; Ruthruff, Johnston, & Van Selst, 2001; Schumacher, Seymour, Glass, Kieras, & Meyer, 2001; Van Selst et al., 1999; Voelcker-

26 12 Rehage & Alberts, 2007), no studies have empirically examined the relationship between effort and attention before and after training in rehabilitation populations. One contribution of this study would be to look at effort and attention before and after an efficacious rehabilitation therapy. The most common way that changes in attention are examined is by using a dual task (cognitive and motor tasks) paradigm (Yap & van der Leij 1994). In these paradigms, a secondary task is added to a primary task and the resultant effect on both tasks is examined. In general, if two tasks require more attentional resources than available, the performance of either or both tasks will deteriorate. The process by which dual-attention tasks are theorized to work is illustrated in Figure 3, which details performance resource functions for two tasks, A and B. Task A demands fewer resources to reach performance levels that are equivalent to B. Task A differs from B by being of lesser difficulty or being less effortful and requiring less attention. An important implication of the Figure 3 is that to fully appreciate the extent of changes in attentional demands, it is necessary to combine a primary task (i.e., the task of interest) with a secondary task (i.e., exceed attentional resources) and then investigate any changes in task performance for one or both tasks. In this example, the less attentionally demanding (Task A) would show less degradation than the more attentionally demanding (Task B), because it requires less overall attentional resources to achieve optimal performance.

27 13 Figure 3. Performance resource function: Task A requires less attentional resources to achieve optimal performance at an equivalent level of performance to Task B. Adapted from Attention, Time-Sharing, and Workload by C. D. Wickens and J. G. Hollands, 1999, Engineering Psychology and Human Performance, p Effort and Motor Rehabilitation Although the question of the relationship of mental and physical effort to motor activity is of basic interest, researchers know very little about how patient engagement affects physical rehabilitation outcomes. Neither do researchers understand how the effort applied to move a paretic arm changes in response to an efficacious treatment. Lastly, researchers know very little about the relationship between how effortful it is move an extremity and its motor capacity or actual use in daily life. A literature review of studies about effort and rehabilitation supports these points. For instance, a systematic literature search of the PubMed (1950 to October 2014), PsycINFO (1953 to October 2014), and Medline (1950 to October 2014) databases using the terms effort, exertion, and fatigue in combination with exercise, motor, and physical and with stroke, rehabilitation, and neurorehabilitation produced less than 30 references

28 14 relevant to these questions. Only one exploratory study provided empirical data on changes in effort, the focus of this study, after physical rehabilitation (Daly, Fang, Perepezko, Siemionow, & Yue, 2006). It reported preliminary data that underlines the need for further research on effort, stroke, and rehabilitation outcomes. Specifically, Daly and colleagues found that the amount of cognitive effort, defined as the motor-related cortical potential amplitude, positively correlates with degree of upper-extremity motor impairment. Another key finding is that physical rehabilitation reduces the amount of perceived effort required to produce and control upper-extremity movement in acute stroke patients. In contrast to previous studies on effort, this dissertation investigated perceptual and physiological dimensions of effort, i.e., perceived effort and sympathetic nervous system activity, using a subjective self-report and cardiovascular responses (SBP and HR), in response to increasing levels of task difficulty before, during, and after CI therapy, an efficacious behavioral-based form of physical rehabilitation, in a much larger sample size (e.g., n = 3 vs. n = 38). A systematic literature search on the same databases using the terms physical rehabilitation and dual-attention produced less than 50 articles, the great majority of which focused on the lower extremities after neurological injury. A cognitive and motor dual-task paradigm was used by most of these studies. For example, Bensoussan and colleagues (2007) reported that sway path of standing hemiplegic patients increased significantly (p <.017) during an arithmetic task but not for age and sex-matched healthy controls. In another representative study, Theil and colleagues (2011) found that gait velocity was reduced (p <.001) for older adults and fewer numbers counted (p <.03) during a working memory arithmetic task. Another key finding was that cognitively

29 15 impaired individuals had lower baseline gait velocity and a greater reduction in gait velocity but not cognitive performance during the dual task than healthy controls (p <.01). In addition to dual-task paradigms as a research method, dual attention tasks have been included as items of functional outcome measures (Lord & Rochester, 2005; Yang et al., 2007a) and as physical rehabilitation techniques (Yang et al., 2007b). For example, Yang and colleagues reported that gait performance for chronic stroke subjects improved after a 4-week dual task exercise program compared to no treatment controls (p <.01), but did not compare dual to single task practice. In contrast to previous dual-attention literature, this dissertation focused on attention and effort for upper-extremity motor activity before and after CI therapy, an efficacious physical rehabilitation treatment. Specific Aims The principle aim of this study was to test whether CI therapy results in reduction in effort required to use the more-affected arm and makes use of the more-affected arm less attentionally demanding. An additional aim was to test whether the amount of effort required to use the more-affected arm and the degree to which more-affected arm use requires less attention are associated with more-affected arm use in daily life. Positive answers to these questions would provide suggestive evidence that reducing effort required to use the more-affected arm is one of the mechanisms by which CI therapy produces large gains in more-affected arm use in daily life. Moreover, positive answers would suggest that researchers undertake studies on directly manipulating effort with the purpose of enhancing rehabilitation outcomes. Specific Aim 1. To test whether effort required to move the more-affected arm, as measured by SBP, HR, and CR10, was correlated with a) how rapidly patients can move

30 16 their more-affected arm in laboratory testing and b) how much patients use their moreaffected arm in everyday life before treatment with CI therapy. Hypothesis 1. Before treatment, there would be a strong, inverse correlation between how effortful it was to move the more-affected arm and the arm s motor capacity and actual use in daily life across all participants. In healthy adults, there is abundant and growing evidence that effort increases with task difficulty (e.g., Gendolla & Wright, 2005). There is also evidence that certain cardiovascular responses, e.g., SBP and HR, vary with effort. Therefore, it was hypothesized that perceived effort and cardiovascular measures of effort, i.e., SBP and HR, would be inversely correlated with a) more-affected arm motor capacity, as assessed by Wolf Motor Function Test Performance Time scores (Morris et al., 2001) and b) more-affected use in daily life, as assessed by Motor Activity Log Arm Use scores (Uswatte et al., 2006). Specific Aim 2. To test whether an efficacious form of upper-extremity rehabilitation, i.e., CI therapy, produces reductions in how effortful it is move the more-affected arm in stroke survivors and individuals with MS. Hypothesis 2. CI therapy patients relative to control participants at the same level of task difficulty would show reduced effort on both self-report and cardiovascular measures. As noted, structural imaging techniques show substantial increases in contralateral primary sensorimotor cortex and motor areas anterior to these loci, equivalent changes in the ipsilateral cortex, and the hippocampus after CI therapy (Gauthier et al., 2008; Mark et al., 2014). It is thought that a mechanism responsible for the large gains in everyday use of the more-affected arm may be that these structural brain changes make movement of the more-affected arm less effortful. Therefore, it was

31 17 hypothesized that CI therapy patients would demonstrate reduced levels of effort after treatment as measured by cardiovascular and self-report indices. Specific Aim 3. To test whether use of the more-affected arm during upper-extremity tasks would require less attention after CI therapy. Hypothesis 3. CI therapy patients would show less degradation of performance on a dual-attention task relative to the control group at the same level of task difficulty. The most widely accepted way to think about dual-task interference is to assume that people share processing capacity among tasks. When more than one task is performed, there is less capacity for each individual task, and performance is impaired. When that happens, more effort is required, and performance on one or both may be degraded (Pashler, 1994; Bensoussan et al., 2007). Therefore, it was hypothesized that CI therapy patients would show less degradation in performance on a dual-attention task from pre-to-post therapy compared to control participants.

32 18 Methods Participants This study enrolled 38 participants at the University of Alabama at Birmingham. Participants were 21 stroke patients (median age = 58.8 years, range = 32-94; 12 females) and 17 MS patients (median age=48.1 years, range= 36-60; 12 females) drawn from two ongoing clinical trials. Both the stroke and MS patients had mild-to-moderate upperextremity hemiparesis. Stroke patients were randomized to home-based, automated CI therapy or standard CI therapy. MS patients were randomized to standard CI therapy or Complementary Alternative Medicine (i.e., massages, relaxation techniques, water and land based yoga and Pilates; CAM). The inclusion/exclusion criteria for this study were not different from the parent CI therapy studies, except for excluding patients on beta-blockers. Participants had substantially reduced use of their more affected arm as indicated by a score on the Motor Activity Log < 2.5 in the case of stroke patients and < 3 in the case of MS patients. Minimum motor criteria were either shoulder flexion and abduction > 45º, elbow extension > 20º from a 90º flexed starting position, wrist extension > 20º, finger extension of all metacarpophalangeal and interphalangeal (either proximal or distal) joints > 10º, and thumb extension or abduction > 10º. These inclusion criteria identified patients who might be characterized as having mild to moderate arm motor deficits, or Grade 2, in the categorization of severity of deficit used in this laboratory. Principal exclusion criteria were (a) inability to complete the 3-step command from the Folstein Mini-Mental State Examination, i.e., inability to understand and follow verbal directions, (b) unstable medical condition, and (c) condition other than stroke that might affect arm

33 19 function. Spinal cord strokes were also excluded from the study. Patients on betablockers (stroke, n = 6; MS, n = 1) were excluded since these drugs interfere with the cardiovascular responses to be measured during the effort testing. Data from 3 pilot participants with stroke were excluded from the pre- to post-treatment analyses, because these adults had already received CI therapy. Table 1 summarizes participant characteristics. The institutional review board of the University of Alabama at Birmingham approved the study procedures, and all participants gave informed consent.

34 Table 1. Gender, Race, and Age at Entry and Neurologic Characteristics of Stroke Patients and Multiple Sclerosis Patients CI therapy Control Characteristic All (N =38) Stroke (n=21) MS (n =9) MS (n =8) Age Mean years ± SD Range, years Female, n (%) 24 (63) 12 (60) 8 (89) 20 4 (50) Race, n (%) European American 25 (66) 12 (60) 7 (78) 6 (75) African American 11 (29) 8 (38) 2 (22) 1 (13) Other 2 (5) 1 (5) 0 (0) 1 (13) Paresis of prestroke dominant side, n (%) 16(42) 10 (50) 2 (22) 4 (50) 20

35 21 Apparatus. The experimental task was to move a peg from a starting hole to a target hole and back on a pegboard before a timer runs out. The pegboard (Figure 4) included three rows of six holes each; each row was for a different sized peg. The participant used the largest peg and its corresponding row. The participant moved the peg from a first hole to the target hole (indicated by a green LED light) and then back to the original hole (indicated by another green LED light) within a given time bin. For example, for the first level, participants had 10 s to complete the sequence of movements described above. Each peg had a magnet in its base, which was also used to collect data on the total number of movements per time bin. Figure 4. Pegboard motor task with arrows indicating both directions of movement. An orange peg marks the target hole. Measures. Physiological indices of effort, systolic BP and HR, were determined during a upper-extremity motor task (i.e., moving pegs). Effort was also measured with the Category Ratio Scale (CR10). The Motor Activity Log (MAL) and Wolf Motor Function

36 22 Test (WMFT) were used as standard outcome measures for CI therapy. Each of these measures is described briefly below. Cardiovascular Measures. SBP is the maximum pressure exerted following a heartbeat (the pressure at the peak of a pulse). HR refers to the pace at which the heart pumps. These two cardiovascular measures were recorded using the Vasotrac noninvasive blood pressure monitoring system on average, every 15 seconds. The Vasotrac monitor has been compared to both a radial artery catheter (Belani et al., 1999; Cua, Thomas, Zurakowski, & Laussen, 2005; Hager et al., 2009) and arm cuff BP (Thomas, Winsor, Pang, Wedel, & Parry, 2005) in various settings and found to have in general an excellent agreement with them. These cardiovascular parameters are expected to better function as indices of effort exerted than reading from other physiological systems, because other physiological systems are not as relevant to the mobilization process. As mentioned previously, effort effects are probably mediated via activity in the sympathetic branch of the nervous system, and an increase in sympathetic activity usually induces simultaneous elevations in SBP and HR (e.g., Gendolla & Wright, 2005). Category Ratio Scale. The CR10 is a well-validated self-report measure of perceived exertion used in physical rehabilitation (Borg, 1998). It is a general intensity scale with values from 1-10 constructed so that measurement is on a ratio scale. The CR10 is derived directly from Borg s Rating of Perceived Exertion (RPE) scale, a reliable and valid ordinal scale of perceived exertion (Borg, 1970). The CR10 scale was developed using scaling methods such as ratio estimation and magnitude estimation (Borg, 1982). The number of inferences and statistical procedures that can be carried out with data from this scale is much greater than the Borg RPE scale (Borg, 1998). Along

37 23 with general instructions, complementary instructions for the modality tested (e.g., perceived exertion, pain, or effort) must be given (Borg, 1998). The CR10 can also be adapted to different modalities, in this case, for physical and mental effort (see Appendix B). Motor Activity Log. The Motor Activity Log (MAL) is a structured, therapistadministered interview of how well and how often a patient uses their more-affected arm for 30 significant and frequently performed activities of daily living (i.e., brushing teeth, dressing; see Appendix A; Uswatte et. al, 2006). The patient responds on a Likert scale ranging from 0 to 5, indicating how successful the weaker arm was for performing each activity during a specified period of time (lower numbers indicate less movement). The MAL is a highly reliable and valid measure of real-world arm use and correlates well with objective measures of arm use in the life situation (Uswatte, Taub, Morris, Vignolo, & McCulloch, 2005; Uswatte et al., 2006). Wolf Motor Function Test. The Wolf Motor Function Test is a validated and reliable objective measure of in-laboratory motor ability involving movements made on request as rapidly and well as the patient can perform (Morris et al., 2001; Wolf et al., 2001). The test items consist of 15 timed motor movements, which range from involving the whole arm to detailed fine motor movements. Time to complete each of 15 upperextremity movements or tasks is recorded. For the purpose of data analysis, the test score is the mean of the item Performance Time scores after transforming them into a rate (repetitions/minute). A a functional ability score, which reflects the quality of movement of the more-affected arm, can also be obtained from this test but is not reported here.

38 24 Procedure Participants with stroke and MS were recruited from two separate RCTs. In the stroke RCT, participants were randomized to standard CI therapy or Tele-AutoCITE. In the MS RCT, participants were randomized to CI therapy or CAM treatments. Each of the interventions is described below. Standard CI Therapy. Stroke and MS patients assigned to standard CI therapy received face-to-face, in-laboratory training of more-affected arm use following shaping principles for 30 hours over two weeks. The therapist provided 3 hours/day of task practice for 10 consecutive weekdays. A padded mitt was placed on the less-affected hand to discourage its use for a target of 90% of waking hours for the two weeks. The therapists also administered a package of behavioral techniques for an additional 0.5 hr/day (e.g., keeping a daily diary, negotiating behavioral contracts) designed to transfer gains from the treatment setting to daily life. Home-based Automated CI Therapy. TeleAutoCITE participants received the same treatment but at home on a workstation with 11 upper-extremity tasks (Uswatte et al., 2013). These tasks were threading a string through holes on raised pegs, raising arm (alternating buttons, lower then higher buttons), reaching, tracing (letter, horizontal, vertical), finger tapping, flipping blocks, and turning hand. A custom software package tracked the participants performance, provided feedback, and paced therapy. A trainer in the laboratory supervised subjects via an internet-based audiovisual and data link. Complementary Alternative Medicine. These treatments were holistic physical treatments designed to work on the entire body to improve quality of life and overall health. This study used yoga, relaxation exercises, aquatherapy (pool therapy), and

39 25 massage. Treatments were given for the same amount of time as for the CI therapy groups. Effort Testing. Perceived effort and sympathetic nervous system activation were assessed before and after CI therapy or CAM treatments. (See Appendix B for the specific CR10 format used.) Testing was done using a paradigm adapted from a wellestablished line of research on effort and cardiovascular responses based on Brehm s Motivational Intensity Theory (Wright, 1996). A range of cardiovascular responses, including SBP and HR were collected using the Vasotrac APM205A non-invasive blood pressure monitoring system. Subjective ratings of perceived effort were measured using the CR10. These data were collected during a ten-minute baseline and a series of six work periods with five interpolated three-minute rest periods. In the first four work periods, participants moved a peg from a starting hole to a target hole and back with their more-affected arm for 60 s on an automated pegboard. Conditions were made more difficult by having participants move the peg to the target and back at progressively faster rates, i.e., every 10, 5, 3, and 2 seconds, respectively. The number of trials per condition, therefore, was 6, 12, 20, and 30, respectively. The rate of movement was controlled by lights that illuminated next to the target hole. A threeminute rest period was provided in-between tasks. In the easiest version of the task, for example, participants were asked to move a peg from a starting hole to a target hole and back 5 times with their more-affected arm within a 60 s period. In the most difficult version, participants were asked to move the peg 30 times with their more-affected arm for 60 s.

40 26 To evaluate whether use of the arm requires less attention after CI therapy, participants were also asked to complete a dual-attention task. Individual components of the dual-task were conducted separately first. In the fifth work period, participants were asked to count upwards by threes, and in the sixth work periods, participants were asked to 1) count upwards by threes and 2) complete the pegboard task while counting upwards by threes. All participants were informed that if they are at least 70% successful at the task at hand (i.e., pegboard task, counting task, or dual-task) during a work period, they will receive $2, i.e., a modest incentive. In the first pegboard work period, this meant that they had to successfully complete at least 5 of the 6 trials. In the counting task work period, this meant that they give at least 26 correct sequences (e.g., 3-6, 6-9 would be 2 correct sequences). The number of correct sequences was counted by two independent raters from videotape. Inter-rater reliability for counting the number of correct sequences was high, r, median =.99, range = (See Appendix E for task instructions with incentives.) As noted, stroke and MS patients were drawn from two ongoing RCTs. The manipulation of difficulty level and manipulation of single vs. dual-task performance were analyzed as two separate studies. For stroke patients that received either homebased Tele-AutoCITE or standard CI therapy, the manipulation of task difficulty levels was analyzed as a 2 (pre vs. post) x 5 (baseline and levels 1-4) factorial, while the manipulation of single vs. dual-task performance was analyzed as a 2 (pre vs. post) x 2 (single- vs. dual-task). For MS patients who received either standard CI therapy or CAM treatments, the task difficulty levels were analyzed as a 2 (pre vs. post) x 2 (therapy vs. control) x 5 (baseline plus levels 1-4) factorial, while the dual-task performance was

41 27 analyzed as a 2 (pre vs. post) x 2 (therapy vs. control) x 2 (single- vs. dual-task). CI Therapy versus CAM was a between subjects factor, while the other factors were withinsubject. Data Reduction For SBP and HR, four samples were typically recorded during each 60 s work period. Only three minutes of samples were recorded during the 10 minute baseline period, since the first 6 minutes and last one minute were discarded to avoid contamination of data at rest by adjustment to the baseline period and anticipation of the end of the baseline. The summary variable values for SBP and HR for the work and rest periods were the average of the sample values recorded except when artifacts were present. In that case, cardiovascular artifacts were extracted from the data set and replaced based on rules for processing cardiovascular data developed by the UAB CI Therapy Research Group with the consultation of Dr. Wright (see Appendix C). Cardiovascular safety guidelines were also developed and produced by the UAB CI Therapy Research Group (see Appendix D). To examine whether data for stroke and MS patients could be collapsed, a repeated measures ANOVA was conducted with all participants. Changes from baseline in perceived effort required to move the more-affected arm during a motor task, as measured by the CR10, varied with diagnosis, F(4, 128) = 4.5, p <.01. The mean CR10 response at pre-treatment across the first four work periods for the stroke patients was ; the corresponding value for the MS patients was In addition, the correlation between HR response and WMFT Performance Rate at pre-treatment varied with diagnosis, p <.01; the coefficient was.41 and -.61 for stroke and MS patients,

42 28 respectively. Because perceived effort to complete the motor tasks and the association between effort required to move the more-affected arm and its motor capacity differed between stroke and MS patients, data from the two patient populations were analyzed separately. Data from the two CI therapy groups in the stroke study were collapsed since their MAL and WMFT results and effort response profiles were similar. Data from subjects who received and did not receive incentives during task performance were collapsed since their effort response profiles were similar. Data Analysis Specific Aim 1. To test whether effort required to move the more-affected arm after CI therapy was correlated with a) how much patients use their more-affected arm in everyday life and b) how rapidly patients can move their more-affected arm. Pearson correlations were used to examine the relationship between how effortful it is to move the more-affected arm and its motor capacity and actual use in daily life across participants at pre-treatment. For each index of effort, the difference between baseline and each task difficulty was calculated level (e.g., average SBP values for task difficulty level 1 minus baseline values), and the average of these differences was used to represent the amount of effort exerted. Thus, effort was operationalized as the average SBP, HR, and CR10 response to a set of upper-extremity motor challenges. Separate correlational models were specified to examine the association of each of these indices of effort with the measures of arm use, i.e., MAL, and motor capacity, WMFT. To account for inflation of family-wise error due to multiple tests, the α value was corrected to.017 per the Bonferroni method. SBP, HR, and CR10 responses and MAL and WMFT scores greater than 2 SDs from the mean were considered outliers and excluded from this and all

43 29 subsequent analyses. The correspondence among the three indices of effort was examined using an approach similar to the one described for testing this aim. The association between pre- to post-treatment changes in the effort indices and corresponding changes in the MAL and WMFT were also examined. In this case, partial correlation models were used in which the post-treatment values of an effort index and motor test were entered as correlates, and the pre-treatment values of these variables were entered as covariates. Specific Aim 2. To test whether upper-extremity rehabilitation, i.e., CI therapy, produces reductions in how effortful it is to move the more-affected arm in stroke survivors. The primary hypothesis was that CI therapy would result in large reductions in how effortful it was to move the more-affected arm. The anticipated result was reduced perceived effort and cardiovascular responsiveness in the CI therapy groups relative to the control groups at the same level of task difficulty. For the stroke sample, separate 2 x 5 repeated measures analyses of variance (ANOVA), were used to study pre- to posttreatment changes in each of the three indices of effort. For example, the average of the SBP values for baseline and four task difficulty levels from each Testing Occasion (Pre, Post) were entered into a repeated measures ANOVA. The effect of interest was the Testing Occasion x Task Difficulty interaction. The same Bonferroni correction was applied as in evaluating Specific Aim 1. For the MS sample, a similar approach was used with exception that a between-subjects factors was added, i.e., group. In this case, the primary effect of interest was the Testing Occasion x Task Difficulty x Group interaction. Specific Aim 3. To test whether use of the more-affected arm during upperextremity tasks requires less attention after CI therapy. The degree to which movement of the more-affected arm was automatic was assessed by the performance cost imposed

44 30 by doing cognitive and motor tasks at the same time (dual-task condition) versus at separate times (single-task condition). To this end, the number of correct sequences was recorded for the cognitive task, i.e., counting up by 3s. For the motor task, i.e., moving a peg, the number of trials that stroke patients completed successfully was recorded. The cognitive and motor task scores were then multiplied and log transformed for single- and dual-task conditions. Performance cost was calculated by taking the difference between log transformed scores from the single- and dual-task conditions. The statistical models used to test whether there were changes after treatment in performance were similar to those used to evaluate Specific Aim 2. To examine pre- to post-treatment changes in effort for the single- versus dualtask paradigm, the average of the effort index values for the motor and cognitive task when performed separately was used to represent effort expended for the single-task condition. The effort index value when the two tasks were performed together, i.e., the dual-task condition, was compared to this average. The statistical models were also similar to those used to evaluate Specific Aim 2.

45 31 Study 1: Adults with Stroke Improvements After CI Therapy in Everyday Arm Use and Arm Motor Capacity In the RCT comparing Tele-AutoCITE to standard CI therapy in stroke patients with mild-to-moderate upper-extremity hemiparesis, participants in both groups showed very large gains in everyday more-affected arm use as measured by the MAL, F(1, 14) = 200.5, p <.0001, d' = 2.9. The convention in the meta-analysis literature is to consider d'=.57 as large (Cohen, 1988). Patients, on average, improved from 1.2 (very poor) to 3.6 (fair to almost normal) on the Arm Use scale. The patients showed moderate gains (d' =.4) in more-affected arm motor capacity, as measured by Performance Rate on the WMFT, F(1, 14) = 7.9, p <.05. There were no significant differences in gains between the groups on the MAL or WMFT. Hence, data from both groups was collapsed. Table 2 summarizes the outcomes. Table 2. MAL and WMFT Scores in Stroke Patients in Tele-AutoCITE or Standard CI Therapy Measure Pre-treatment Post-treatment Change d' Note. Values are mean (SD). CI therapy (n = 15) MAL, 0-5 points 1.2 (0.6) 3.6 (1.0) 2.4 (0.9) 2.9 WMFT, repetitions/minute 28.4 (12.2) 34.3 (14.6) 5.8 (8.0) 0.4 Abbreviations: CAM, complementary alternative medicine; MAL, Motor Activity Log; WMFT, Wolf Motor Function Test Variation in the Indices of Effort with Levels of Task Difficulty A manipulation check of the data was performed to determine if effort and task difficulty increased concomitantly. As Figure 5 shows at pre-treatment each of the indices of effort increased monotonically with task difficulty, p s <.001.

46 32 A Heart Rate (BPM) Task Difficulty Level B. Category Ratio Scale (0-10 points) Task Difficulty Level C. Systolic Blood Pressure (mm Hg) Task Difficulty Level Figure 5. Relationship in stroke patients at pre-treatment between task difficulty and effort indices A. systolic blood pressure B. heart rate C. Category Ratio Scale. One-way repeated measures ANOVA revealed significant mean differences between levels for systolic blood pressure, F(4, 60) = 6.7, p =.002, heart rate, F(4, 60) = 8.6, p <.0001, and the Category Ratio Scale, F(4, 68) = 28.5, p < Abbreviations: mmhg, millimeters of mercury; BPM, beats per minute; ANOVA, analysis of variance

47 33 Relationships Before CI Therapy Among the Three Indices of Effort To examine the relationships among the three indices of effort, correlations among the cardiovascular measures, i.e., SBP and HR, and CR10 ratings, were calculated. For each index, the difference between baseline and each task difficulty level was calculated, and the average of these differences was entered into the correlation matrix. The largest correlation was observed between SBP and CR10 responses, r(15) =.66, p <.01. The correlations for HR response with CR10 and SBP responses were weak, r(15) =.17, p =.55 and r(15) =.07, p =.80, respectively. Figure 6 shows the scatterplot of the relationship between SBP andcr10 responses. Systolic Blood Pressxure (mm Hg) 7 r(16) =.66, p< Category Ratio Scale (0-10 points) Figure 6. Relationship in stroke patients at pre-treatment between perceived effort (Category Ratio Scale) and systolic blood pressure. Values plotted are average differences between four difficulty levels and baseline. Abbreviations: mmhg, millimeters of mercury

48 34 Relationships Before CI Therapy Between Effort and Everyday Arm Use and Arm Motor Capacity The average change in values for SBP, HR, and the CR10 for the four difficulty levels, relative to baseline, was calculated, and resultant response values were used to calculate correlations between the three indices of effort and the measures of A) everyday more-affected arm use, i.e., MAL, and B) more-affected arm motor capacity, i.e., WMFT. Table 3 lists the correlations at pre-treatment for SBP, HR, and CR10 with scores on the MAL and WMFT. Contrary to expectations, none of the correlations among the indices of effort and the MAL or WMFT were significant.

49 35 Table 3. Pearson Correlations at Pre-treatment for SBP, HR, and CR10 Responses with the MAL and WMFT MAL WMFT Outliers removed Systolic blood pressure Pearson correlation p-value n Heart rate Pearson correlation p-value n Category Ratio Scale Pearson correlation p-value n All participants Systolic blood pressure Pearson correlation p-value n Heart rate Pearson correlation p-value n Category Ratio Scale Pearson correlation p-value n Note. No significant correlations among SBP, HR, and CR10 with the MAL Arm Use and WMFT Performance Rate were found. SBP and HR readings were taken on average 3.3 times per minute. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Moto Function Test; CR10, Category Ratio Scale; SBP, systolic blood pressure; HR, heart rate

50 36 Effect of CI Therapy on Effort Expended on the Motor Task For both stroke patients that received home-based Tele-AutoCITE or standard CI therapy, changes from baseline in perceived effort required to move the more-affected arm during a motor task, as measured by the CR10, depended on the interaction between difficulty level of the task and testing occasion, F(4, 56) = 3.3, p<.02, =.19. For values of.02,.13, and.26 are considered small, medium, and large, respectively (Cohen, 1988; Miles & Shevlin, 2001). At post-treatment, the differences between perceived effort for the high difficulty levels (3 and 4) and low difficulty levels (1 and 2) were greater than at pre-treatment. The interaction effects for SBP and HR responses were not significant, and none of the main effects of testing occasion were significant. However, the main effects of task difficulty on effort were large and were significant (CR10, HR) or approached significance (SBP) after correcting for multiple comparisons: CR10, F(4, 56) = 35.8, p <.0001, =.72; HR, F(4, 44) = 9.7, p <.0001, =.47;F(4, 44) = 3.2, p =.02, =.23. In other words, the effort indices increased monotonically with task η p 2 η p 2 difficulty when the data were collapsed across testing occasion, i.e., pre- and posttreatment. This result is consistent, of course, with the manipulation check that showed a similar pattern at pre-treatment only. Figure 7 compares the changes relative to baseline in the effort indices at pre- and post-treatment for the four progressive levels of task difficulty. η p 2 η p 2 η p 2

51 37 A. Systolic Blood Pressure (mm Hg) Task Difficulty Level Pre-treatment Post-treatment B Heart Rate (BPM) Pre-treatment Post-treatment Task Difficulty Level C. Category Ratio Scale (0-10 points) Task Difficulty Level Pre-treatment Post-treatment Figure 7. Relationship in stroke patients at pre- and post-treatment between task difficulty and effort indices A. systolic blood pressure B. heart rate C. Category Ratio Scale. Abbreviations: mmhg, millimeters of mercury; BPM, beats per minute

52 38 Table 4 lists the partial correlations of post-treatment SBP, HR, and CR10 response values with scores on the MAL and WMFT, using pre-treatment values of these variables as covariates. None of the correlations among pre- to post-treatment changes in the indices of effort and corresponding changes in the MAL or WMFT were significant. However, the correlation between MAL Arm Use scores and HR was large, and the sign was in the expected, negative direction, r(12) = -.48, p =.16. Subjects with the largest pre- to post-treatment impairments on the MAL had the largest decreases in HR. Figure 8 depicts this relationship.

53 39 Table 4. Partial Pearson Correlations at Post-treatment for Systolic SBP, HR, and CR10 Responses with the MAL and WMFT, using Pre-treatment Scores as Covariates MAL WMFT Outliers removed Systolic blood pressure Pearson correlation p-value n Heart rate Pearson correlation p-value n Category Ratio Scale Pearson correlation p-value n All participants Systolic blood pressure Pearson correlation p-value n Heart rate Pearson correlation p-value n Category Ratio Scale Pearson correlation p-value N Note. No significant correlations among SBP, HR, and CR10 with MAL Arm Use and WMFT Performance Rate were found. SBP and HR readings were taken on average 3.2 times per minute. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test; CR10, Category Ratio Scale; SBP, systolic blood pressure; HR, heart rate

54 40 10 MAL Arm Use Change r(12) = -.48, p= Heart Rate Change Figure 8. Relationship in stroke patients between pre- to post-treatment changes in heart rate and MAL Arm Use scores. Change Score values are the residuals from regressing post-treatment scores on pre-treatment scores. Post-treatment and pre-treatment scores are the average of four difficulty levels from baseline. Outliers are removed. Abbreviations: MAL, Motor Activity Log Effect of CI Therapy on Automaticity of Task Performance As noted, the degree to which movement of the more-affected arm was automatic, i.e., required less attention, was assessed by the performance cost imposed by doing cognitive and motor tasks at the same time (dual-task condition) versus at separate times (single-task condition). To this end, the number of correct sequences was recorded for the cognitive task, i.e., counting up by 3s, and the number of trials that stroke patients completed successfully for the motor task, i.e., moving a peg, was recorded. The cognitive and motor task scores were then multiplied and log transformed for single- and dual-task conditions. Performance cost was calculated by taking the difference between log transformed scores from the single- and dual-task conditions. For both stroke patients

55 41 that received home-based Tele-AutoCITE and standard CI therapy, performance became more automatic after treatment, i.e., the difference in performance between the singleand dual-task conditions depended on testing occasion, F(1, 11) = 5.5, p =.04, d =.8 Performance improved on the dual-task; the gap from the scores from the single- and dual-task conditions narrowed by 0.19 ± There was also a main effect of type of task, F(1, 11) = 16.2, p =.002. The main effect of testing occasion was not significant. Figure 9 shows how performance varied with condition and testing occasion and the interaction between the two. 2.6 Performance Scores Pre Testing Occasion Post Single Dual Figure 9. Relationship in stroke patients under single- and dual-task conditions between performance and testing occasion. The performance score is the log the product of the cognitive and motor task scores. The log was taken to normalize the distribution. Note. *Indicates a significant result at p <.05. Table 5 lists the correlations at pre-treatment between the performance cost imposed by the dual- versus single-task condition and the MAL and WMFT. Table 6 list the partial correlation between performance cost and MAL and WMFT scores at post-

56 42 treatment, using pre-treatment values of these variables as covariates. None of the correlations between performance and the MAL or WMFT at pre-treatment were significant. Neither were any of the correlations between pre- to post-treatment changes in performance cost and MAL or WMFT scores.

57 43 Table 5. Pearson Correlations at Pre-treatment Between Performance Cost of the Dualvs. Single-task Condition and the MAL and the WMFT MAL WMFT All participants Performance cost Pearson correlation p-value n Note. The correlations were not significant. Performance cost in the log of the product of cognitive and motor performance in the dual-task condition minus the corresponding quantity under the single-task condition. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test Table 6. Partial Pearson Correlations at Post-Treatment Between Performance Cost of the Dual- vs. Single-task Condition and MAL and WMFT, using Pre-Treatment Scores as Covariates MAL WMFT Outliers removed Performance cost Pearson correlation p-value n All participants Performance cost Pearson correlation p-value n Note. The correlations were not significant. Performance cost in the log of the product of cognitive and motor performance in the dual-task condition minus the corresponding quantity under the single-task condition. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test

58 44 Effect of CI Therapy on Effort Expended on Dual- Versus Single-tasks of CI Therapy on Effort Expended on Dual- Versus Single-tasks To calculate SBP, HR, and CR response for the single- versus dual-task paradigm, the average of the effort index values for the motor and cognitive task when performed separately was used to represent effort expended for the single-task condition. The effort index value recorded when the two tasks were performed together, i.e., the dual-task condition, was compared to this average. In other words, the single-task condition was treated as the baseline. For both stroke patients that received home-based Tele- AutoCITE or standard CI therapy, perceived effort for the dual-task relative to single-task condition fell from pre- to post-treatment, F(1, 12) = 14.3, p =.003, =.54. In addition, there was a main effect of type of task (single vs. dual) on perceived effort, F(1, 12) = 56.7, p <.0001, =.83; perceived effort was greater for the dual- than single-task η p 2 condition when data were collapsed across testing occasion. The main effect of testing occasion was not significant, i.e., perceived effort did not change from pre- to posttreatment when data were collapsed across type of task. Figure 10 shows how perceived effort varied with condition and testing occasion and the interaction between the two. There were no significant main or interaction effects for the physiological indices of effort. η p 2

59 45 Category Ratio Scale (0-10 points) Pre Testing Occasion Post Single Dual Figure 10. Relationship in stroke patients under single- and dual-task conditions between Category Ratio Scale and testing occasion. Perceived effort, as measured by CR10, for single-task conditions were calculated as the average of the ratings for the individual tasks when performed separately. Note. *Indicates a significant result at p <.05. Abbreviations: CR10, Category Ratio Scale Table 7 lists the correlations at pre-treatment for SBP, HR, and CR10 dual-task values, relative to the single-task condition, with scores on the MAL and WMFT. None of the correlations among any of the indices of effort and the MAL and WMFT were significant after correcting for multiple comparisons. For the measure of everyday use, the MAL, the magnitude and sign of the correlations varied considerably; the largest correlation was between HR and the MAL, r(11) = -.54, p =.11. For the measure of motor capacity, the WMFT, the magnitude of the correlation between SBP and WMFT was strong and the sign negative, i.e., in the expected direction, r(10) = -.58, p =.08.

60 46 Table 7. Pearson Correlations at Pre-treatment for SBP, HR, and CR10 for the Dual-task Condition with the MAL and WMFT MAL WMFT Outliers removed Systolic blood pressure Pearson correlation p-value n Heart rate Pearson correlation p-value n 10 9 Category Ratio Scale Pearson correlation p-value n All participants Systolic blood pressure Pearson correlation p-value n Heart rate Pearson correlation p-value n Category Ratio Scale Pearson correlation p-value n Note. No significant correlations among SBP, HR, and CR10 and MAL Arm Use and WMFT Performance Rate were found. Effort index values for the dual-task condition were expressed as the change from the single-task condition when calculating these correlations. SBP and HR readings were taken on average 3.0 times per minute. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test; CR10, Category Ratio 10 Scale; SBP, systolic blood pressure; HR, heart rate

61 47 Table 8 lists the partial correlations between post-treatment SBP, HR, and CR10 values for the dual-task condition, relative to single-task condition, using corresponding pre-treatment values as covariates. None of the correlations among any of the indices of effort and the MAL or WMFT were significant. For the MAL the magnitude and sign of the correlations varied considerably; the magnitude of the correlation between SBP and MAL was strongest and the sign negative, i.e., in the expected direction, r(9) = -.68, p =.09. For the measure of arm motor capacity, the WMFT the magnitude of the correlation between SBP and WMFT was strong and negative, r(8) = -.78, p =.07, which was similar to the result for the MAL. Figure 11 depicts these strong relationships.

62 48 Table 8. Partial Pearson Correlations at Post-treatment for SBP, HR, and CR10 for the Dual-task Condition with MAL and WMFT, using Corresponding Pre-Treatment Scores as Covariates MAL WMFT Outliers removed Systolic blood pressure Pearson correlation p-value n 9 8 Heart rate Pearson correlation p-value n 8 7 Category Ratio Scale Pearson correlation p-value n All participants Systolic blood pressure Pearson correlation p-value n 9 9 Heart rate Pearson correlation p-value n 9 9 Category Ratio Scale Pearson correlation p-value n No significant correlations among SBP, HR, and CR10 and MAL Arm Use and WMFT Performance Rate were found. Effort index values for the dual-task condition were expressed as the change from the single-task condition when calculating these correlations. SBP and HR readings were taken on average 3.0 times per minute. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test; CR10, Category Ratio Scale; SBP, systolic blood pressure; HR, heart rate

63 49 15 MAL Arm Use Change 10 r(9) = -.68, p= Systolic Blood Pressure Change 15 WMFT Performance Rate Change 10 r(8) = -.78, p= Systolic Blood Pressure Change Figure 11. Relationship in stroke patients between pre- to post-treatment changes in systolic blood pressure and A. MAL Arm Use scores B. WMFT Performance Rate. Change Score values are the residuals from regressing post-treatment scores on pretreatment scores. Effort index values for the dual-task condition were expressed as the change from the single-task condition when calculating these correlations. Outliers are removed. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test.

64 50 Relationship Between Automaticity and Effort for the Dual-task Condition Table 9 lists the correlations at pre-treatment for the indices of effort, i.e., SBP, HR, and CR10 response values, with the index of automaticity, i.e., performance cost. None of the correlations among any of the indices of effort and the index of automaticity were significant after correcting for multiple comparisons, which set α to.017. However, the magnitude of the correlation between SBP and performance cost was strongest and the sign positive, i.e., in the expected direction, r(11) =.66, p =.03. Figure 12 depicts this relationship. Table 9. Pearson Correlations at Pre-treatment for SBP, HR, and CR10 Responses with Performance Cost Performance Cost Outliers removed All participants Systolic blood pressure Pearson correlation p-value n Heart rate Pearson correlation p-value n Category Ratio Scale Pearson correlation p-value n Note. No significant correlations among SBP, HR, and CR10 and the MAL Arm Use and WMFT Performance Rate were found. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test; CR10, Category Ratio Scale; SBP, systolic blood pressure; HR, heart rate

65 51 r(11) =.66, p= Systolic Blood Pressure (mmhg) Performance Cost Figure 12. Relationship in stroke patients at pre-treatment between systolic blood pressure and performance cost. Performance costs are calculated as difference in the log of the product of motor and cognitive performances from single- to dual-task conditions. Outliers are removed. Abbreviations: mmhg, millimeters of mercury

66 52 Study 2:Adults with Multiple Sclerosis Improvements in Everyday Use and Motor Capacity of the More-affected Arm after CI Therapy In the RCT comparing standard CI therapy to CAM treatments in MS patients with mild-to-moderate upper-extremity hemiparesis, everyday more-affected arm use, as measured by the MAL, improved substantially more in the CI therapy than CAM group. In other words, there was a significant interaction between treatment group and testing occasion, F(1, 15) = 44.0, p <.0001, =.75. CI therapy participants showed very large MAL gains, F(1, 8) = 151.6, p <.0001, d' = 4.6. This group, on average, improved from 1.8 (poor) to 4.3 (almost normal to normal) on the Arm Use scale. CAM participants, who received massage or yoga showed substantially smaller MAL gains, F (1, 7) = 7.5, p <.05, d' =.6. This group, on average, improved from 1.6 (very poor to poor) to 2.2 (poor) on the Arm Use scale. Participants, regardless of the treatment to which they had been assigned, showed similar pre- to post-treatment improvements in more-affected arm motor capacity as measured by Performance Rate score on the WMFT, F(1, 15) = 15.8, p <.01, =.51. The CI therapy group gain in Performance Rate was 5.9, F(1, 8) = 10.4, η p 2 η p 2 p <.05, d' =.8. The CAM group gain was 7.5, F(1, 7) = 6.6, p <.05, d' =.7. Notably, these gains although large (d' >.57), were substantially smaller than the gains observed on the MAL. None of the interaction effects or effects of group, i.e., treatment assignment, on Performance Rate scores were significant. Table 10 summarizes the outcomes.

67 53 Table 10. Mean MAL and WMFT Scores for MS Patients in CI Therapy and CAM Treatment Groups Measure Pre-treatment Post-treatment Change d' CI therapy (n = 9) MAL, 0-5 points 1.8 (0.6) 4.3 (0.8) 2.5 (0.6) 4.6 WMFT, repetitions/minute 40.8 (5.0) 46.7 (8.7) 5.9(5.4) 0.8 Complementary alternative medicine (n = 8) MAL, 0-5 points 1.6 (0.7) 2.2 (1.0) 0.6(0.6) 0.6 WMFT, repetitions/minute 33.1 (11.0) 40.5 (9.9) 7.5(8.2) 0.7 Note. Values are mean (SD). Abbreviations: CAM, complementary alternative medicine; MAL, Motor Activity Log; WMFT, Wolf Motor Function Test Variation of the Indices of Effort with Levels of Task Difficulty A manipulation check of the data was performed to determine if both effort and task difficulty increased concomitantly. As Figure 13 shows each of the indices of effort increased monotonically with task difficulty, p s <.05.

68 54 A. Systolic Blood Pressure(mm Hg) Task Difficulty Level B. 12 Heart Rate (BPM) Task Difficulty Level C. Category Ratio 10 (0-10 points) Task Difficulty Level Figure 13. Relationship in multiple sclerosis patients at pre-treatment between task difficulty and effort indices A. systolic blood pressure B. heart rate C. Category Ratio Scale. One-way repeated measures ANOVA revealed significant mean differences between levels for systolic blood pressure, F(4, 56) = 3.6, p =.011, heart rate, F(4, 60) = 9.9, p <.0001, and Category Ratio Scale, F(4, 64) = 31.6, p < Abbreviations: mmhg, millimeters of mercury; BPM, beats per minute; ANOVA, analysis of variance

69 55 Relationships Before Treatment Among the Three Indices of Effort The correlations for HR response with SBP and CR10responses were moderate with positive signs, r(14) =.28, p =.33 and, r(15) =.46, p =.09, respectively. Contrary to expectations, the smallest correlation was observed between SBP and CR10, r(15) = -.05, p =.87. Relationships Before Treatment Between Effort and Everyday Arm Use and Arm Motor Capacity Table 11 lists the correlations at pre-treatment of SBP, HR, and CR10 responses with scores on the MAL and WMFT. None of the correlations among any of the indices of effort and the MAL were significant. However, for the measure of motor capacity, the WMFT, the correlation with HR response was strong and significant, r(16) = -.61, p =.01. Figure 14 shows a scatterplot of the relationship between HR response and scores on the MAL and WMFT.

70 56 Table 11. Pearson Correlations at Pre-treatment of SBP, HR, and CR10 Responses with MAL and WMFT MAL WMFT Outliers removed Systolic blood pressure Pearson correlation p-value n Heart rate Pearson correlation p-value.17.01* n Category Ratio Scale Pearson correlation p-value n All participants Systolic blood pressure Pearson correlation p-value n Heart rate Pearson correlation p-value n Category Ratio Scale Pearson correlation p-value n Note. *Correlation is significant at p < 0.01 (alpha =.05, 2-tailed). Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test; CR10, Category Ratio Scale; SBP, systolic blood pressure; HR, heart rate

71 57 A. 3 MAL Arm Use Scores (0-5 Points) r(16) = -.36, p= Heart Rate (BPM) B. 60 WMFT Performance Rate (s) r(16) = -.61, p=.01* Heart Rate (BPM) Figure 14. Relationship in MS patients between heart rate response and A. MAL Arm Use scores and B. WMFT Performance Rate. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test; BPM, beats per minute; MS, Multiple Sclerosis

72 58 No Effect of CI Therapy on Effort Expended on the Motor Task For both MS patients that received standard CI therapy or CAM treatments, the main effect of task difficulty on effort was large and significant after correcting for multiple comparisons: CR10, F(4, 60) = 62.3, p<.0001, =.82; SBP, F(4, 52) = 8.1, p<.0001, =.35; HR, F(4, 56) = 17.4, p <.0001, =.55. In other words, the effort η p 2 indices increased monotonically with task difficulty when data were collapsed across treatment group and testing occasion. These results are consistent with the manipulation check analysis showing monotonic relationships between the indices of effort and task difficulty at pre-treatment. Contrary to expectations, none of the interaction effects, effects of type of treatment, or effects of testing occasion were significant. Figure 15 compares the changes relative to baseline in the effort indices at pre- and post-treatment for CI therapy and CAM groups for the four progressive levels of task difficulty. η p 2 η p 2

73 CI Therapy Complementary Alternative Medicine A. Systolic Blood Pressure (mm Hg) Task Difficulty Level B. Systolic Blood Pressure (mm Hg) Task Difficulty Level C. 12 D. 12 Heart Rate (BPM) Heart Rate (BPM) Task Difficulty Level Task Difficulty Level 59

74 E. 6 F. Category Ratio Scale (0-10 points) Task Difficulty Level Category Ratio Scale (0-10 points) Task Difficulty Level Figure 15. Relationship in MS patients at pre- and post-treatment between task difficulty and effort indices A. systolic blood pressure B. heart rate C. Category Ratio Scale. Outliers are removed. Bars in blue represent pre-treatment data. Bars in red represent post-treatment data. Abbreviations: mmhg, millimeters of mercury; BPM, beats per minute; MS, Multiple Sclerosis 60

75 61 Table 12 lists the partial correlations of post-treatment SBP, HR, and CR10 responses with scores on the MAL and WMFT, using pre-treatment values as covariates. None of the correlations among pre- to post-treatment changes in the indices of effort and corresponding changes in the MAL or WMFT were significant. However, the correlation between MAL Arm Use scores and SBP was moderate, and the sign was in the expected, negative direction, r(15) = -.43, p =.14.

76 62 Table 12. Partial Pearson Correlations at Post-treatment of SBP, HR, and CR10 Responses with MAL and WMFT, using Pre-Treatment Scores as Covariates MAL WMFT Outliers removed Systolic blood pressure Pearson correlation p-value n Heart rate Pearson correlation p-value n Category Ratio Scale Pearson correlation p-value n All participants Systolic blood pressure Pearson correlation p-value n Heart rate Pearson correlation p-value n Category Ratio Scale Pearson correlation p-value n Note. No significant correlations among SBP, HR, and CR10 with MAL and WMFT were found. Systolic blood pressure and heart rate readings were taken on average 3.2 times per minute. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test; CR10, Category Ratio Scale; SBP, systolic blood pressure; HR, heart rate

77 63 Tables 13 lists the partial correlations of post-treatment SBP, HR, and CR10 responses with scores on the MAL and WMFT, using pre-treatment values as covariates, for the CI therapy group only. Table 14 does the same for the CAM group only. None of the correlations among pre- to post-treatment changes in the indices of effort and corresponding changes in the MAL or WMFT were significant. However, for the CI therapy group the correlation between MAL Arm Use scores and CR10 was strong and the sign in the expected direction: r(6) = -.94, p =.06. Figure 16 depicts this relationship.

78 64 Table 13. Partial Pearson Correlations at Post-treatment of SBP, HR, and CR10 Responses with MAL and WMFT, using Pre-Treatment Scores as Covariates, for MS Patients in CI Therapy Group MAL WMFT Outliers removed Systolic blood pressure Pearson correlation p-value n 7 8 Heart rate Pearson correlation p-value n 9 9 Category Ratio Scale Pearson correlation p-value n 6 7 All participants Systolic blood pressure Pearson correlation p-value n 8 8 Heart rate Pearson correlation p-value n 9 9 Category Ratio Scale Pearson correlation p-value n 7 7 Note. No significant correlations among SBP, HR, and CR10 with MAL and WMFT were found. Systolic blood pressure and heart rate readings were taken on average 3.2 times per minute. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test; CR10, Category Ratio Scale; SBP, systolic blood pressure; HR, heart rate

79 65 2 MAL Arm Use Change 1.5 r(6) =--.94, p= Category Ratio Scale Change Figure 16. Relationship in MS patients in the CI therapy group between pre- to posttreatment changes in CR10 responses and MAL Arm Use scores. Change Score values are the residuals from regressing post-treatment scores on pre-treatment scores. Posttreatment and pre-treatment scores are the average of four difficulty levels from baseline. Outliers are removed. Abbreviations: MAL, Motor Activity Log; CR10, Category Ratio Scale

80 66 Table 14. Partial Pearson Correlations at Post-treatment of SBP, HR, and CR10 Responses with MAL and WMFT, using Pre-Treatment Scores as Covariates, for MS Patients in CAM Therapy MAL WMFT All participants Systolic blood pressure Pearson correlation p-value n 8 8 Heart rate Pearson correlation p-value n 8 8 Category Ratio Scale Pearson correlation p-value n 8 8 Note. No significant correlations among SBP, HR, and CR10 with MAL and WMFT were found. There were no outliers. Systolic blood pressure and heart rate readings were taken on average 3.2 times per minute. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test; CR10, Category Ratio Scale; SBP, systolic blood pressure; HR, heart rate; CAM, complementary alternative medicine No Effect of CI Therapy on Automaticity of Task Performance For both patients that received standard CI therapy or CAM treatments, there was a main effect of type of task, F(1, 7) = 16.6, p <.01, =.75. Task performance degraded under the dual-task relative to single-task condition. None of the other interaction effects, main effects of testing occasion, or main effects of group were significant. Figure 16 shows how performance varied with task for CI therapy and CAM subjects. η p 2

81 CI Therapy Complementary Alternative Medicine A. B Performance Scores Pre Post Testing Occasion Sing Dua Performance Scores Pre Testing Occasion Post Single Dual Figure 17. Relationship in stroke patients under single- and dual-task conditions between performance and testing occasion for A. CI therapy B. CAM treatments. The performance score is the log the product of the cognitive and motor task scores. The log was taken to normalize the distribution. Abbreviations: CAM, complementary alternative medicine 67

82 68 Table 15 lists the correlations at pre-treatment between the performance cost imposed by the dual- versus single-task condition and the MAL and WMFT. As noted, a small performance cost imposed by the dual- relative to single-task condition is thought to reflect automatic performance of the tasks. Table 14 lists the partial correlation between performance cost and MAL and WMFT scores at post-treatment, using pretreatment values of these variables as covariates. The largest correlation, which was not in expected direction, was between the automaticity index and the WMFT performance rate, r(9) =.68, p =.09. None of the correlations between performance and the MAL or WMFT at pre-treatment were significant. Neither were any of the correlations between pre- to post-treatment changes in performance cost and MAL or WMFT scores. Table 15. Pearson Correlations at Pre-treatment Between Performance Cost of the Dual- Versus Single-task Condition and the MAL and the WMFT MAL WMFT All participants Performance cost Pearson correlation p-value n 9 9 Note. The correlations were not significant. Performance cost in the log of the product of cognitive and motor performance in the dual-task condition minus the corresponding quantity under the single-task condition. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test

83 69 Table 16. Partial Pearson Correlations at Post-Treatment Between Performance Cost of the Dual- versus Single-task Condition and MAL and WMFT, using Pre-Treatment Scores as Covariates MAL WMFT All participants Performance cost Pearson correlation p-value n 9 9 Note. The correlations were not significant. Performance cost in the log of the product of cognitive and motor performance in the dual-task condition minus the corresponding quantity under the single-task condition. Abbreviations: MAL, Motor Activity Log; WMFT, Wolf Motor Function Test No Effect of CI Therapy on Effort Expended on Dual- Versus Single-tasks For both MS patients that received standard CI therapy or CAM treatments, there was a main effect of type of task (single- vs. dual-task) on perceived effort, as measured by the CR10, F(1, 7) = 41.0, p <.001, η p 2 =.82. Perceived effort increased under the dual-task relative to single-task condition. None of other effects of task, interaction effects, effect of group, or effect of testing occasion were significant. Figure 18 shows how perceived effort varied with task and testing occasion and the interaction between the two for CI therapy and CAM subjects. There were no significant main effects for the physiological indices of effort.

84 CI Therapy Complementary Alternative Medicine A. Category Ratio Scale (0-10 points) Pre Post Single Dual B. Category Ratio Scale (0-10 points) Pre Post Single Dual Testing Occasion Testing Occasion Figure 18. Relationship in MS patients under single- and dual-task conditions between Category Ratio Scale and testing occasion for A. CI therapy B. CAM treatments. Perceived effort, as measured by CR10, for single-task conditions were calculated as the average of the ratings for the individual tasks when performed separately. Abbreviations: CR10, Category Ratio Scale; CAM, complementary alternative medicine 70