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Engagement of the action observation network through functional magnetic resonance imaging with implications for stroke rehabilitation
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Engagement of the action observation network through functional magnetic resonance imaging with implications for stroke rehabilitation
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ENGAGEMENT OF THE ACTION OBSERVATION NETWORK THROUGH FUNCTIONAL MAGNETIC RESONANCE IMAGING WITH IMPLICATIONS FOR STROKE REHABILITATION by Panthea Heydari A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (NEUROSCIENCE) August 2017 Advisory Committee: Lisa Aziz-Zadeh, Ph.D. Carolee Winstein, Ph.D. Hanna Damasio, M.D. ii ACKNOWLEDGEMENTS In the last five years, I have crossed paths with countless individuals. Some of them have been instrumental in my graduate career, others in my professional development, and all in my life trajectory and personal growth. It would be impossible to clearly state the effect of each of these individuals on my personal view of the world, but I will try to acknowledge some of you here and thank you for your time and support during this journey. First and foremost, I would like to start by thanking the patients and participants of this study, for without them this dissertation research would not be possible. I thank you for your time and willingness to participate in our research. I hope that our work can help influence the direction of this field and potentially assist in the development of better methods for recovery of individuals who have suffered a stroke. I would like to thank my mentor, Dr. Lisa Aziz-Zadeh, for your mentorship and drive to shape me into a stronger graduate student, researcher, and member of the USC family. Your assistance in the study design, analysis, and overall insight into the field of cognitive neuroscience have greatly influenced and shaped my graduate career. Thank you for your relentless pursuit of science, enthusiasm, and engaging and positive attitude. Additionally, I would like to thank the members of my advisory committee: Dr. Bosco Tjan, Dr. Hanna Damasio, Dr. Carolee Winstein, and Dr. Paul Thompson. A great portion of this study would be impossible without the guidance of the late Dr. Bosco Tjan. Bosco, thank you for teaching me the fundamentals of functional neuroimaging and helping me design this study with thought provoking questions in mind-- we miss you dearly. Hanna, thank you for being one iii of the highest caliber neuroimagers of our time and constantly motivating me to go to the next level in my research. Carolee, thank you for your insight on recovery and rehabilitation, as well as our discussions on career trajectories and the state of clinical research, in general. Paul, thank you for your positive attitude and support during the planning and data acquisition phases of this study. To my colleagues, supporters, and friends, past and present, at the Brain and Creativity Institute, I am forever grateful. Thank you to Drs. Hanna and Antonio Damasio for creating this institute and allowing for incredible science and friendships to take place. Dr. Helder Araujo, I cannot image getting through graduate school without you—thank you for your ears, our rooftop conversations, and your insight into this thing we call life. Dr. Sarah Gimbel, thank you for always having an open-door policy and pushing me out of my comfort zone. Dr. Assal Habibi, thank you for talking politics and DTI whenever I came knocking. Dr. Kingson Man, thank you for our discussions and adventures both inside and outside the walls of the BCI. Dr. Jonas Kaplan, thank you for your incredible help in data analysis and patience with me as I learned to code. Dr. Julie Werner, I do not think I can fully express how important your support and assistance have meant to me; thank you for your patience, your knowledge, and your sharing of Huxley. We have come a long way from those downtown adventures, but I would not trade it for anything else. Additional thanks go out to members of the BCI for your influence in my graduate career and for making me laugh and learn along the way: Dr. Morteza Dehghani, Dr. XiaFei Yang, Dr. Glenn Fox, Dr. Mona Sobhani, Dr. Sook-Lei Liew, Dr. Kathleen Garrison, Matt Sachs, Jared Gilbert, Rodrigo Miranda, Alissa Der Sarkissian, Ryan Veiga, Cara Fesjian, Gil Blank, Faith Ishibani, Denise Nakamura, and Cinthya Nunez. iv Thank you to the members of the A-Z Lab: Emily Kilroy, Dr. Laura Harrison, Christiana Butera, Elizabeth Goo, Jennifer Sprawls, Krupa Patel, and all the research associates who made me remember the joys of teaching and mentorship. I look forward to seeing you develop at the BCI and am grateful to have had your support. A most heartfelt thank you and much appreciation goes out to the Neuroscience Graduate Program advisors, faculty, administrators, and students. Specifically, Drs. Pat Levitt and Judith Hirsch, thank you for creating an environment where students can pursue their passion and excel in their field. Thank you to my NGP friends and family: Brian Leung, thank you for our swim days and for keeping me on board with the latest scientific inquiries; Nick Goeden, thank you for our conversations on science, gaming, and life; and Helga Mazyar, thank you for being my Iranian partner at USC and for your kindness. Also, I would like to thank NGP administrators, Ariana Perez and Dawn Burke, for making the program run so smoothly. Thank you to other members of the NGP 2012 (and other year) cohorts for your friendship and support over the last five years. I would like to thank the funding agencies that made this research possible: National Institute of Health and the Dana and David Dornsife Foundation. Specifically, I would like to thank the National Science Foundation for the honor of being selected as a recipient of the Graduate Research Fellowship Program (NSF GRFP). This fellowship provided me with three years of funding as well as travel and cost of education funds that allowed me to expand not only my scientific knowledge, but also develop lasting collaborations with other leading scientists, administrators, and writers. Thank you for selecting me as part of the NSF GRFP. v Outside of my relationships developed at USC, I would also like to thank friends and family that have listened to me discuss my scientific work, running interests, and love of corgis throughout my chapter at USC and, likely, into the next few chapters. Thank you to my Neuro Lady Crew: Dr. Natalie Kintz, thank you for your kind heart and always helpful advice; Dr. Madeline Andrews, thank you for your adventurous spirit and love of science; Dr. Jillian Shaw, thank you for being my climbing buddy and always just a phone call away. I would like to thank my friends in the SoCal Coyotes for our trail conversations, explorations, and adventures. Thank you for getting me out of the lab and helping me stay balanced. A great deal of support in these last few years came from my partner, Marshall Howland. Marshall, thank you for being the best boyfriend and partner; thank you for your kindness, knowledge, laughter, and for always believing that I would succeed. I am so grateful to you. Finally, I would like to thank my family; thank you to my parents for your support and always believing in me. Thank you to Clay Turner, for giving me that business perspective and being a dear friend. Most of all, a great thank you to my sisters, Dr. Andia Turner and Anaheed Heydari. I am forever grateful for our triangle. I left the acknowledgements to be the last thing I wrote and, as I assess the incredible number of people that have gone into making this dissertation a reality, I am beyond grateful. I am grateful to have such an incredible support system. I am grateful for my mentors, colleagues, friends, partners, and family. Thank you for being a part of this journey. vi TABLE OF CONTENTS LIST OF FIGURES viii LIST OF TABLES ix CHAPTER ONE: INTRODUCTION TO THE ACTION OBSERVATION NETWORK AND STROKE 1 Mirror Neuron System and the Action Observation Network 2 Discovery of the Mirror Neuron System 2 Properties of Mirror Neurons 3 The Putative Human Mirror Neuron System 5 Neuroimaging Evidence for the Human MNS 6 The Action Observation Network 9 Imitative Learning and the AON 9 Stroke and the Action Observation Network 11 Action Observation Therapy 12 Addressing the Gap in Knowledge 13 REFERENCES 22 CHAPTER TWO: ACTIVITY PATTERNS IN THE MOTOR REGIONS OF CHRONIC STROKE PATIENTS DURING ACTION OBSERVATION, EXECUTION, AND IMITATION OF UPPER EXTREMITY MOVEMENTS 38 INTRODUCTION 38 METHODS 42 Subjects 42 Functional Neuroimaging: fMRI 42 fMRI Analysis 46 RESULTS 49 Whole brain fMRI Results 50 Region of Interest BOLD Signal Change Results 52 Brain Behavior Analyses 53 DISCUSSION 55 LIMITATIONS AND FUTURE DIRECTIONS 57 CONCLUSIONS 59 REFERENCES 70 CHAPTER THREE: ENGAGEMENT OF THE ACTION OBSERVATION NETWORK FOR LOWER EXTREMITY ACTIONS IN INDIVIDUALS WITH STROKE 80 INTRODUCTION 80 METHODS 84 Subjects 84 Functional Neuroimaging: fMRI 85 fMRI Analysis 88 RESULTS 91 vii Whole brain fMRI Results 91 Region of Interest percent BOLD Signal Change Results 96 Brain Behavior Results 96 DISCUSSION 97 LIMITATIONS AND FUTURE DIRECTIONS 99 CONCLUSION 101 REFERENCES 116 CHAPTER FOUR: CONCLUSION 126 ENGAGEMNET OF THE AON FOR UE 126 ENGAGEMENT OF THE AON FOR LE 128 DIFFERENCES BETWEEN THE UE AND LE 129 FUTURE DIRECTIONS 130 REFERENCES 132 APPENDIX 137 APPENDIX A: BEHAVIORAL ASSESSMENTS 137 APPENDIX B: ANALYSIS PROTOCOL 195 viii LIST OF FIGURES Figure 1.1 Homology between the macaque frontal lobe and human frontal cortex 19 Figure 1.2 Examples of areas of the Action Observation Network 20 Figure 2.1 Main effect of Action Observation 60 Figure 2.2 Lesion Masks of Individuals with Stroke 61 Figure 2.3 Whole brain activity during left and right hand action observation, execution And imitation for non-disabled and individuals with stroke 62 Figure 2.4 Whole brain activity during left and right hand subtraction contrasts 63 Figure 2.5 (Supplementary) Stimuli for fMRI study of the AON for Upper Extremity 64 Figure 3.1 Stimuli for fMRI Study of the AON for Lower Extremity 102 Figure 3.2 Lesion Mask of Individuals with Lower Extremity Stroke 103 Figure 3.3 Whole brain activity during left and right hand observation, execution, and Imitation for non-disabled and individuals with stroke affecting lower extremity 104 Figure 3.4 Whole brain activity overlap for left and right action execution – observation Of the lower extremity (LE) for non-disabled and individuals with stroke 105 Figure 3.5 (Supplementary) Score Sheet for Fugl-Meyer Assessment Lower Extremity 107 Figure 4.1 AON extremity-specific engagement during action observation 134 Figure 4.2 AON extremity-specific engagement during action execution 135 Figure 4.3 AON extremity-specific engagement during action imitation 136 ix LIST OF TABLES Table 1.1 Neuroimaging modalities provide different types of information 21 Table 2.1 Demographics of Stroke and Non-Disabled groups 65 Table 2.2 Demographics and Lesion Information of Stroke group 66 Table 2.3 Main effect contrast of execution – observation for left and right hand actions 67 Table 2.4 Main effect contrast of imitation-execution for left and right hand actions 68 Table 2.5 Percent BOLD Signal Change within ROI 69 Table 3.1 Demographics of Stroke and Nondisabled groups 108 Table 3.2 Demographics and lesion information of stroke group 109 Table 3.3 Main effect of action observation of left and right foot actions 110 Table 3.4 Main effect of action execution of left and right actions 111 Table 3.5 Main effect of action imitation of left and right foot actions 112 Table 3.6 Brain activity compared between action execution and action observation Of left and right foot actions 113 Table 3.7 Percent BOLD Signal Change within ROI 114 Table 3.8 Brain Behavior correlation of percent BOLD signal change within ROI 115 1 CHAPTER ONE: INTRODUCTION TO THE ACTION OBSERVATION NETWORK AND STROKE Motor deficits are a major contributor to functional disability in the approximately 800,000 people per year who suffer from a new or recurrent cerebrovascular accident (CVA) in the U.S. (Kochanek SL; Xu JQ, Arias E., 2014). CVAs, or strokes, result from an ischemic or hemorrhagic lesion in the brain that can cause damage to the underlying neural tissue. Ischemic strokes, accounting for 87% of all strokes, are caused by an interruption or lack of the blood supply to a brain region through a cerebral venous sinus or peripheral thrombosis, embolism, or hypoperfusion (Donnan et al., 2008; Stam, 2005). Hemorrhagic strokes, accounting for 13% of strokes, result from bleeding into the brain due to a ruptured blood vessel or an abnormal vascular structure. Both types of strokes typically result in brain damage of the white matter tracts, such as the corticospinal tract (Rüber et al., 2012; Wang et al., 2016). Damage to this tract may result in motor deficits such as hemiplegia, muscle weakness, and flaccidity or spasticity of the paretic limb (Donnan et al., 2008). Clinical rehabilitative efforts to improve motor deficiency focus traditionally on stimulating the use of the paretic limb in order to provide possibly experience-dependent positive neuronal plasticity and, thus, promote motor recovery (Grefkes & Fink, 2011; Rossetti, Rode, & Goldenberg, 2005). In individuals with mild- to-moderate motor impairment, such movements may be executable; however, in individuals with little residual motor capability, such movements may be much more challenging (Garrison, Aziz-Zadeh, Wong, Liew, & Winstein, 2013; Liew, Garrison, & Werner, 2012). Consequently, additional forms of rehabilitation that engage the premotor and motor neural networks, 2 required for movement planning and movement execution, respectively, need to be considered. There is increasing evidence suggesting that the engagement of brain regions when individuals are asked to observe an action (“action observation”) is similar to the engagement of the same brain regions when the individual is asked to execute the action (“action execution”) (Gallese, Fadiga, Fogassi, & Rizzolatti, 1996; Rizzolatti, 2005; Rizzolatti & Fogassi, 2014; Rizzolatti, Luppino, & Matelli, 1998). Such engagement may potentially allow additional neural plasticity. Consequently, engagement of this motor and premotor network may promote recovery and change in functional motor behavior. The neurophysiological basis for the overlap between action observation and execution is based on the cooperation of different brain regions known as the Mirror Neuron System (MNS). Mirror Neuron System and the Action Observation Network Discovery of the Mirror Neuron System The mirror neuron system (MNS), first discovered in the monkey through single-cell recordings from surgically implanted microelectrodes, consists of a set of premotor and parietal neurons that discharge when the macaque performs a goal-oriented action, as well as when it observes another agent performing a similar action (di Pellegrino, Fadiga, Fogassi, Gallese, & Rizzolatti, 1992; Gallese et al., 1996; Rizzolatti & Craighero, 2004). These neurons were originally identified in the ventral premotor cortex (area F5) of the macaque and have since also been described in the prefrontal gyrus (PFG) and anterior intraparietal (AIP) areas of the inferior parietal lobule (IPL) (Fadiga et al., 1999; Gallese et al., 1996; Rizzolatti, 2005). In the 3 monkey, hand-specific neurons discharged during both the active hand movements by the monkey and during observation of meaningful hand movements by the experimenter (di Pellegrino et al., 1992). Laterally in F5, such neurons were also described for mouth related actions (Ferrari, Gallese, Rizzolatti, & Fogassi, 2003). These neurons were coined “mirror neurons” (Gallese et al., 1996; G Rizzolatti & Craighero, 2004). Properties of Mirror Neurons Mirror neurons are generally goal-oriented, visuo-motor congruent (respond to visually similar or conceptually related observed and executed actions), and discharge during observation of a part of an action (Umiltà et al., 2001) or in response to a sound associated with a particular action (Keysers et al., 2003; Kohler et al., 2002). The Mirror Neuron System (MNS) is considered to be an observation-execution matching system (Gallese et al., 1996; Rizzolatti & Fogassi, 2014): mirror neurons fire in response to both the observation and execution of goal-oriented actions. One example of such a goal-directed action is the grasping of objects, e.g. for eating; mirror neurons fire regardless of the hand being open or closed during a reach towards a food item (Aziz-Zadeh, Wilson, Rizzolatti, & Iacoboni, 2006; Cattaneo & Rizzolatti, 2009; Rizzolatti et al., 1988, 1998, Umiltà et al., 2001, 2008). Mirror neurons have distinct visual properties; they are responsive to position in space, hand use (right versus left), and direction of movement (Gallese et al., 1996). Studies investigating peripersonal versus extrapersonal space in primates suggest a visual response to action location in space for some mirror neurons (Caggiano, Fogassi, Rizzolatti, Thier, & Casile, 2009). Some of these space-selective neurons are engaged in space-encoding for a fixed 4 boundary between self and the object (metric space), or for a dynamic boundary that depends on ability to reach the object (operational space). Mirror neuron preference for different perspectives of grasping objects further supports visual specificity of these neurons (Matelli, Camarda, Glickstein, & Rizzolatti, 1986). The functional implication of these view-dependent neurons is thought to be linked to the understanding of the goals associated with an action. A higher order feedback mechanism between the anterior superior temporal sulcus and F5, through indirect prefrontal cortex pathways, allow for these visual-specific neurons to “understand goals” associated with an action (Borra et al., 2008; Rozzi, Ferrari, Bonini, Rizzolatti, & Fogassi, 2008). Mirror neurons have been hypothesized to be involved in understanding the subject- specific value of grasped objects because activity of the MNS is modulated by the “value” of the observed action. Several studies suggest an increased percentage of electrophysiological neuronal responses for mirror neurons during grasping of food versus an object devoid of value to the animal. Some mirror neurons have a stronger visual response for reward-associated grasped objects (Ferris et al., 2012) than others. The subjective value of an object, e.g. a peanut for a macaque or a specific type of dance for human dancers, may be of importance to these subjects’ mirror neurons. These neurons also respond to auditory sounds of specific motor acts, e.g. breaking peanuts or ripping a piece of paper (Kohler et al., 2002). Mirror neurons are also involved in the abstract coding of actions; they fire during observation of grasping and for the view of a goal-specific grip, even if the ending of the action itself is not observed by the subject (Umiltà et al., 2001). Such studies provide evidence for the theory of mirror neuron involvement in understanding an action when visually or auditorily presented. 5 Functional imaging studies in the macaque (Nelissen et al., 2011; Nelissen & Vanduffel, 2011) have shown a frontoparietal network engagement during action observation, which includes the inferior parietal PFG and AIP (anterior intraparietal). Anatomically, the use of injected tracers has demonstrated that both the PFG and AIP are connected to the STS. Two streams of information processing distinguish the response to actions of others: one involves the STS, PFG, and premotor areas F5c and F4; the other involves STS, AIP, and premotor areas F5p and F5a (Rozzi et al., 2006; Borra et al., 2008). Electrophysiological studies show that grasping mirror neurons are found in the posterior bank of inferior arcuate sulcus and the adjacent cortex, specifically in the F5-AIP circuit. The motor properties of MNS neurons are the same among brain regions, yet the sensory properties among these areas are different (Gallese et al., 1996). Modern comparative anatomical and histological studies (Figure 1) indicate that the human homologue to area F5 of the monkey is the pars opercularis of the IFG (Bonin & Illinois, 1947; Rizzolatti & Craighero, 2004; von Economo, 1929). Studies using functional imaging have identified a human homologue to the macaque mirror neuron system and called it the putative human mirror neuron system. The Putative Human Mirror Neuron System The mirror neuron system has been identified in the macaque through electrophysiological recordings showing responding neurons during both action observation and execution. The ability to conduct such research related single-cell recordings in humans is difficult and limited due to ethical considerations, thus, the search for a putative human mirror 6 neuron system has relied on studies of cytoarchitectural homology between the macaque and the human brains and functional imaging work (Petrides & Pandya, 1994; Petrides, Tomaiuolo, Yeterian, & Pandya, 2012; Rizzolatti & Matelli, 2003). Converging behavioral, neurophysiologic, and functional neuroimaging studies have provided evidence for a human MNS (Rizzolatti & Craighero, 2004). Neuroimaging Evidence for the Human MNS Neuroimaging studies providing evidence for the existence of a putative human MNS include studies of Electroencephalography (EEG), Magnetoencephalographic (MEG), Transcranial Magnetic Stimulation (TMS), Positron Emission Tomography (PET), and functional Magnetic Resonance Imaging (fMRI) (Table 1). Early studies of the motor cortex using EEG showed rhythm desynchronization (Gastaut & Bert, 1954) during the observation of others’ actions. Years later, other investigations further confirmed these findings using EEG (Cochin, Barthelemy, Lejeune, Roux, & Martineau, 1998) and MEG techniques (Hari et al., 1998). Additional work with ERP supplemented such results by showing that mu rhythm at central sites is also desynchronized during observation of others’ actions (Babiloni et al., 2002; Cochin et al., 1998; De Vico Fallani et al., 2009; Oberman, Pineda, & Ramachandran, 2007; Pineda, Allison, & Vankov, 2000). Using transcranial magnetic stimulation (TMS), other researchers investigated motor-evoked potentials (MEPs) while a subject observed an experimenter grasping objects or performing arm gestures and found activity in the contralateral motor cortex (Fadiga, Fogassi, Pavesi, & Rizzolatti, 1995). Furthermore, there was an increase in MEPs within muscles that are used to perform a 7 movement during both observation and execution of actions (Fadiga et al., 1995; Rizzolatti & Craighero, 2004). Strafella and Paus, using double pulse TMS, provided additional evidence in support of cortical mirror neuron activity in the primary motor cortex (Strafella & Paus, 2000). They showed that during action observation, the duration of intracortical recurrent inhibition was the same as during action execution. Activity in the corticospinal tract, and subsequent motor movement in muscles, was measured by the H-reflex in flexor and extensor muscles (Baldissera, Cavallari, Craighero, & Fadiga, 2001). This activity showed that spinal cord excitability changes in a pattern opposite to that of cortical regions: during observation, when the CST fibers are inhibited (so no overt movement can occur), the individual is still able to understand the goal of the action. The motor excitability of the muscle, measured by MEPs, is associated with the grasping action (Gangitano, Mottaghy, & Pascual-Leone, 2001). Positron emission tomography (PET) provides support for cortical engagement of inferior frontal and inferior parietal cortices in the human MNS (Grafton, Fagg, & Arbib, 1998). Brain imaging studies show that action observation engages the rostral part of the IPL, the lower part of the precentral gyrus, and the posterior IFG (Buccino et al., 2004; Decety, Chaminade, Grèzes, & Meltzoff, 2002; Grafton et al., 1998; Iacoboni et al., 1999a; Nishitani & Hari, 1999), in addition to the occipital, temporal, and parietal visual areas. Such studies provide support for the engagement of these cortical regions as the core of the putative human MNS. Functional MRI has been used to provide evidence towards the putative human MNS during conditions of observation, execution, and imitation. Neural brain activity, measured 8 indirectly through the Blood Oxygen Level Dependence (BOLD) signal of fMRI, has supported the notion of mirror regions in humans during action observation, imitation, or execution of finger tapping movements (Iacoboni et al., 1999a). FMRI studies of specific hand and mouth actions also provide support for the MNS. The precentral gyrus (PCG), IFG pars opercularis, and IPL are engaged during transitive mouth actions (Buccino et al., 2001), while dorsal PCG, IFG pars opercularis, and rostral IPL are engaged during hand/arm actions. Observation of actions involving the hand and mouth engages the IFG pars opercularis, while actions involving the more proximal arm and neck engages the PCG (Rizzolatti & Craighero, 2004). Such effector type and location specificity engagement provides additional support for MNS engagement. Engagement of the mirror neuron system during action observation and execution is shown in human neurophysiological and brain imaging studies, as previously described. While these studies provide evidence towards a putative human MNS, recruitment of additional regions allow us to further study differences in task engagement of the recently coined “Action Observation Network”. The AON encompasses a broader network of neural regions involved in visual analysis of action as well as areas involved in visuomotor and sequence learning, including the STS and the dorsal premotor cortices (Grèzes, Armony, Rowe, & Passingham, 2003; Jenkins, Brooks, Nixon, Frackowiak, & Passingham, 1994; Sakai, Ramnani, & Passingham, 2002). In this dissertation, emphasis is given to the AON because the AON encompasses all known brain regions involved in action observation processes, rather than those exclusively engaged for observation and execution only (e.g., inferior parietal and premotor cortices) (Cross, Kraemer, Hamilton, Kelley, & Grafton, 2009). 9 The Action Observation Network The putative human mirror neuron system, engaged during action observation and execution, consists of the frontal gyrus (IFG), ventral premotor cortex (PMv), and inferior parietal lobule (IPL) as mentioned earlier. Additional brain regions show mirror-like properties and are engaged during action observation. These areas include the dorsal premotor cortex (PMd), superior temporal sulcus (STS), superior parietal lobule (SPL), somatosensory cortex (S1), posterior middle temporal gyrus (MTG), and visual area (V5) (Figure 2). Together, these brain regions, are form the Action Observation Network (AON) (Caspers, Zilles, Laird, & Eickhoff, 2010; Rizzolatti & Craighero, 2004). The AON, as discussed in this dissertation, is known to be implicated during both action observation and action execution in the human. It is a multimodal network and it has been shown to be of use for action understanding and inferring the goal of an observed action. It is also engaged in imitative learning, a core form of post-stroke learning (Giovanni Buccino et al., 2004; Ertelt et al., 2007; Ertelt, Hemmelmann, Dettmers, Ziegler, & Binkofski, 2012; Liew et al., 2012). Imitative Learning and the AON Imitative learning in humans is supported by the engagement of motor, premotor, and planning regions, in addition to the AON. In the monkey, evidence exists regarding the ability to imitate movements (Ferrari, Maiolini, Addessi, Fogassi, & Visalberghi, 2005; Subiaul, Cantlon, Holloway, & Terrace, 2004; Visalberghi & Fragasazy, 1990; Voelkl & Huber, 2000; Whiten & Ham, 1992). In humans, fMRI studies show engagement of the AON during observation, 10 execution, and imitation of movements (Buccino et al., 2001; Iacoboni et al., 1999a; Iacoboni, 2005; Jackson, Meltzoff, & Decety, 2006; Keysers & Gazzola, 2009; Koski, Iacoboni, Dubeau, Woods, & Mazziotta, 2003; Rizzolatti, Fogassi, & Gallese, 2002). An additional region implicated in the AON for imitative learning in humans, in addition to premotor and prefrontal regions, is the superior temporal sulcus (STS). While this region is not typically engaged during action execution (the motor cortex is predominately engaged), it has been implicated in imitation (Decety et al., 2002; Iacoboni et al., 1999a). The STS is thought to be used for coding and understanding of visual stimuli (Jellema, Baker, Wicker, & Perrett, 2000; Perrett et al., 1989) and for integrating information. Information regarding object-specific representation is sent from the visual cortices to the IPL, where it is integrated in a motor goal- oriented program, and further relayed to the PMv and IFG (Iacoboni, 2005; Rizzolatti, 2005). Together, premotor cortices, IPL, IFG, and STS are thought to encompass the minimal neural architecture necessary for processing imitation. Imitation learning, believed to be dependent on a combination of observation and execution, engages the IPL, posterior IFG, and ventral PMC (Buccino et al., 2004). Further engagement of the dorsolateral prefrontal cortex (DLPFC) and middle frontal gyrus (MTG) are thought to be involved in the understanding and execution of imitated actions (Vogt et al., 2007). The imitation neural circuit is goal-oriented and action-specific. Overall, humans imitate to a high degree and use the mechanisms of imitation for motor learning (Decety et al., 2002). Consequently, rehabilitation methods involving imitative learning may be of benefit when an individual shows post-stroke deficits (Buccino et al., 2001; Iacoboni et al., 1999a; Iacoboni, 2005; Jackson et al., 2006; Keysers & Gazzola, 2009; Koski et al., 2003; Rizzolatti et al., 2002). 11 Such methods have varying levels of efficacy for recovery of patients. Overlapping engagement during action observation, execution, and imitation in the IFG, PMv, PMd, IPL, SPL, S1, MTG, and V5, can be used to promote neural reorganization and recovery. An assessment of the engagement level of the neural circuit associated with action observation and execution is of paramount importance in recovery. This engagement level can serve as an indicator of patient recovery or a point of reference in determining what type of rehabilitation is best for each individual. Stroke and the Action Observation Network Patients who experience severe hemiparesis and after a stroke may have difficulty performing tasks that are usually part of therapy procedures. Therefore, a possibility to engage the motor system through engagement of the Action Observation Network (AON) may be a useful approach to promote learning of motor skills as a form of rehabilitation in such patients (Buccino, 2014; Garrison et al., 2013). Action observation is believed to help recruit and prime a motor plan that is necessary for later action execution (Flanagan & Johansson, 2003; Flanagan, Vetter, Johansson, & Wolpert, 2003; Stefan et al., 2005). Through engagement of the AON, observation may promote improved recovery post stroke (Ertelt et al., 2007; Huang et al., 2010). Imitation of an action is a complex act requiring complex cognitive function. It begins with observation of another performing an action, continues with the development of a motor plan, and results in execution of a motor output (Garrison et al., 2013; Small, Buccino, & Solodkin, 2012). During imitation, one simultaneously observes and executes as task. The 12 cognitive and motor recruitment necessary for this may be challenging for an individual with limited motor capability. Due to difficulty in the “execution” part of imitation (we are defining “imitation” as simultaneous “observation” plus “execution”), it may be beneficial to engage an individual’s motor network and AON passively, or without overt movement (Coupar, Pollock, Rowe, Weir, & Langhorne, 2011; Garrison et al., 2013; Kitago et al., 2012; Lauretani et al., 2010; Liew et al., 2012; Lindenberg et al., 2010; Sütbeyaz, Yavuzer, Sezer, & Koseoglu, 2007). One such method first utilizes action observation, and is called “Action Observation Therapy”. Action Observation Therapy Action observation therapy (AOT) is a translational rehabilitative approach based on the engagement of the AON. Clinical approaches of AOT include first showing patients a set of videos of object-directed actions, from varying perspectives, and then asking the patients to execute, when possible, what was observed. Engagement of the AON may potentially lead to plasticity of affected cortical regions, resulting in motor changes, and rebuilding of function in individuals after stroke (Pomeroy, 2005). Evidence for the usefulness of AOT as a method of practice in occupational and rehabilitative therapy has been discussed both theoretically (Buccino, 2014; Buccino & Riggio, 2006; Cattaneo & Rizzolatti, 2009; Liew et al., 2012) and empirically (Ertelt et al., 2007; Lauretani et al., 2010). Different studies have used fMRI to show increased BOLD signal during observation of actions in patients after stroke (Cacchio, De Blasis, De Blasis, Santilli, & Spacca, 2009; Carvalho et al., 2013). Priming cortical engagement during observation may allow an individual to have better performance of the task—the intended benefit of AOT. It has been 13 shown that AOT can enhance the effects of occupational and physical therapy, yet, up until now, effects benefits have been modest. The effectiveness of action observation as a supplement to standard upper-limb therapy after stroke has been investigated and found to show some benefits in measures of impairment and functional ability. Investigations of the use of action observation and AOT in individuals with stroke have addressed measurement of brain activity in correlation to primary behavioral motor outcome measures, with mixed results (Buccino & Riggio, 2006; Celnik, Webster, Glasser, & Cohen, 2008; Ertelt et al., 2007, 2012; Franceschini et al., 2012; Iacoboni & Mazziotta, 2007, Cowles et al., 2012; Lauretani et al., 2010). Some of these studies did not show significant differences between the experimental (action observation with movement therapy) and control (movement therapy only) groups, whereas others did show differences. The interpretation of such discrepancies in the effectives of AOT will need to take into consideration the size of the studies, the power of statistical analyses, lesion group differences, and choice of control conditions. While modest improvements in behavioral outcomes of stroke patients with use of AOT are promising, the variability in results raise questions for the efficacy of such therapy. Thus, further studies investigating the neural engagement underlying the AOT (i.e. the AON) are needed before such therapy can be effectively promoted for clinical used. Addressing the Gap in Knowledge While the possibility of using AOT for motor rehabilitation after stroke is promising and potentially beneficial, mixed results from clinical studies do not permit to state unequivocally 14 that there is a benefit of AOT (Cowles et al., 2012; Pomeroy, 2005). There still exists a gap between the basic neurophysiological principles underlying engagement of this network of brain regions and the efficiency of the network in therapeutical practice. Key questions remain: which conditions best engage this system, whether this system is engaged more for one effector (upper extremity) versus another (lower extremity), and what is the correlation between brain structure, function of the network, and behavioral outcome of individuals. Lack of clear answers to these questions may influence clinicians’ ability to determine who will best benefit from such therapies. Therefore, there is a strong need to further explore the engagement of the AON, particularly after stroke, in order to develop AOT adjusted to patients’ need. In this dissertation, I propose neuroimaging studies to address this gap in knowledge. I will investigate (Study 1) how activity in the AON is modulated by the observation of upper extremity actions and which condition (action observation, execution, imitation) show the biggest engagement of the AON in individuals with motor deficits after stroke. I will also investigate (Study 2), what, if any, AON activity can be demonstrated for the lower extremity, and how it differs between individuals with motor deficits after stroke and non-disabled controls. To address each of these questions, I have two studies and two aims: Aim 1: To determine which condition (action observation, execution, or imitation of the upper extremity) engages the AON (inferior frontal gyrus, premotor cortices, inferior parietal lobule, superior temporal sulcus) and/or primary motor cortex (M1) the most. 15 Hypothesis: I predict the observation condition will yield some level of AON activity, followed by a higher level of activity for execution, followed by the most activity for imitation condition (purported simultaneous observation and execution). Previous studies have observed increasing levels of AON engagement for adults in the following order: imitation > execution > observation (Iacoboni et al., 1999a). I predict this pattern of engagement will be seen in the non-disabled adult control group and the experimental group (individuals with stroke affecting the motor activity of the upper extremity (UE)). Rationale: Motor deficits of UE after stroke are a major contributor to disability and decreased quality of life. Action observation and engagement of the AON may promote motor recovery after stroke and result in rehabilitation of UE function. Evidence suggests that older adults can create new motor memories and possibly re-learn motor patterns after a stroke (Buccino et al., 2004; Iacoboni et al., 1999b; Vogt et al., 2007). It is unclear which type of task (observation, execution, imitation) is the most effective in this learning and/or in engaging the AON for potential motor memory formation and stroke rehabilitation. Some believe the most effective way to create motor memories is through imitation; pure observation or execution are not considered as effective (Iacoboni et al., 1999a; Rossini et al., 2007). I will be investigating this relationship with the ultimate hope that the results will help inform and develop protocols of AOT. Approach: I will use fMRI to compare the level of Blood Oxygen Level Dependent (BOLD) signal activity yielded across three conditions (action observation, action execution, action imitation) to find out which condition engages the AON to the highest degree. I will compare the conditions directly and through mathematical estimates, correcting for noise and motion 16 variables. Conditions will be defined as follows: action observation as passive observation of a video-taped action; action execution as execution of a predetermined action (pressing buttons located on a box) using a visual cue; and action imitation as the combination of observation of an action and simultaneous performance of that action. I will use specific subtraction and conjunction contrasts to compare brain activity levels across the conditions. Aim 2: To functionally identify and describe the AON representation for the lower extremity (foot) in individuals with motor impairment in the lower extremity due to damage from stroke and in non-impaired subjects. Hypothesis: I predict action observation and execution for the lower extremity (LE) will engage motor and premotor areas of the AON for the non-disabled group. In the stroke group, I predict AON activity both contralesionally and ipsilesionally. Rationale: Lower extremity function is often associated with walking and movement of an individual though space. Research on AON engagement for actions involving the lower extremity (LE) is limited. In individuals with stroke, motor deficits of the upper and lower extremities are major contributors to functional disability (Kochanek SL; Xu JQ, Arias E., 2014). Garrison et al. show cortical reorganization after stroke during action observation; AON activity in the IFG shifts anteriorly during observation of UE actions and is inversely correlated with functional ability scores (Garrison et al., 2013). Rehabilitation methods to promote recovery include such methods of action observation of UE actions (Ertelt et al., 2012), which is hypothesized to recruit similar brain regions to action execution of UE actions via engagement of the AON (Gallese et al., 1996; Grafton, 2009; Iacoboni & Mazziotta, 2007). Research on AON engagement for actions involving the lower extremity (LE) is limited in 17 stroke patients as well. This hinders the potential application of AOT in patients with motor impairment involving the LE (Burke, Dobkin, Noser, Enney, & Cramer, 2014; Enzinger et al., 2008; Tang et al., 2010). In this study, I will investigate AON engagement for actions involving the foot. Approach: I will use fMRI to determine the engagement of the AON in (a) non-disabled individuals and (b) in individuals with motor impairments affecting the LE. Both groups will watch (action observation) or perform (action execution) movements of plantar flexion with eversion and inversion during a fMRI scan. Stimuli will show, in the first-person perspective, photos or videos of movements in both lower extremities (foot, LE) performed by a non- disabled actor. Participants will either observe or execute the actions seen in the stimuli. To identify the AON in the non-disabled group, I will (1) assess for overlap during conditions of action observation and execution. Previous studies have suggested that for individuals with severe upper extremity (hand, UE) motor impairment (measured by the Fugl-Meyer Upper Extremity (FM-UE) motor score), activity of the AON shifts anterior to the motor and pre-motor cortices in perilesional tissue during action observation (Garrison et al., 2013). I will also (2) assess for overlap of observation and execution to investigate if the same is true for individuals with mild-to-moderate impairment in the LE. The long-term goal of the proposed investigation is to bridge the gap in understanding the neurophysiology and engagement of the AON and to translate this information into clinical utility by investigating questions that can directly inform AOT. Such information can be used in developing therapeutic protocols useful for the promotion of motor recovery after stroke based 18 on neural plasticity, neuro-reorganization, and, therefore, allow for personalized rehabilitation therapies. 19 Figure 1.1. Homology between macaque frontal lobe and human frontal cortex. Homology between the macaque and human cortex here is measured through cytoarchitechtonics, electrical stimulation, and sulci embryology. Figure 1A shows the parcellation of the prearcuate cortex and agranular frontal cortex of the macaque monkey. Figure 1B shows the parcellation of the intermediate precentral cortex (Rizzolatti & Arbib, 1998) 20 Figure 1.2. Examples of areas of the Action Observation Network (AON). BOLD level activity, measured through functional MRI, is compared when an individual observes another grasping an object within context against rest. 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Retrieved from 37 http://jama.jamanetwork.com/article.aspx?articleid=203876 38 CHAPTER TWO: ACTIVITY PATTERNS IN THE MOTOR REGIONS OF CHRONIC STROKE PATIENTS DURING ACTION OBSERVATION, EXECUTION, AND IMITATION OF UPPER EXTREMITY MOVEMENTS INTRODUCTION Stroke is the leading cause of disability in the United States, with motor deficits of the upper extremity as a major contributor to such functional disability (Duncan, Goldstein, Matchar, Divine, & Feussner, 1992; Kochanek SL; Xu JQ, Arias E., 2014; Mozaffarian et al., 2016). Traditionally, clinical rehabilitative efforts to improve upper extremity (UE), or hand, motor deficits have incorporated repetitive use of the paretic limb in order to provide sensory input to promote functional motor recovery, possibly through experience-dependent positive neuronal plasticity (Grefkes & Fink, 2011; Rossetti, Rode, & Goldenberg, 2005). This rehabilitative technique is supported by the motor learning theory, based on empirical evidence that supports specificity, repetition, and salience of movements, in particular, as ways to increase neural plasticity (Kleim et al., 2002; Kleim & Jones, 2008). In individuals with mild- to-moderate motor impairment, such movements may be feasible, however, in individuals with more severe impairment and little residual motor capability, these movements may be much more challenging (Garrison, Aziz-Zadeh, Wong, Liew, & Winstein, 2013; Liew, Garrison, & Werner, 2012). Furthermore, individuals in the chronic phase (defined as 3 months post stroke onset) may have little to no supervised physical or occupational therapy, potentially limiting further recovery (Feigenson, 1981; Jongbloed & Wendland, 2002; Maulden, Gassaway, Horn, 39 Smout, & DeJong, 2005). Consequently, additional forms of rehabilitation that address these challenges have been proposed. One such proposed treatment exists that recruits the motor network without explicit motor movement. Increasing evidence suggests that the same motor regions of the brain that are engaged during execution of actions may also be involved during observation of those same actions (Carvalho et al., 2013; Gallese, Fadiga, Fogassi, & Rizzolatti, 1996; Iacoboni & Mazziotta, 2007; Mukamel, Ekstrom, Kaplan, Iacoboni, & Fried, 2010; Rizzolatti & Craighero, 2004; Giacomo Rizzolatti, Fadiga, Gallese, & Fogassi, 1996; Sale et al., 2012). Engaging these motor brain networks through what is termed “action observation therapy” (AOT) may allow for additional recovery for patients with impairments due to stroke (Buccino & Riggio, 2006; Celnik, Webster, Glasser, & Cohen, 2008; Duncan, Goldstein, Matchar, Divine, & Feussner, 1992; Ertelt et al., 2007; Ertelt, Hemmelmann, Dettmers, Ziegler, & Binkofski, 2012; Franceschini et al., 2012; Iacoboni & Dapretto, 2006; Iacoboni & Mazziotta, 2007). The neural foundation behind a recent therapeutic intervention, AOT, is believed to be what is called the mirror neuron system (MNS). Mirror neurons discharge during execution of a goal-oriented action as well when a subject observes someone else executing the same or similar action (di Pellegrino, Fadiga, Fogassi, Gallese, & Rizzolatti, 1992; Gallese et al., 1996; Rizzolatti, Luppino, & Matelli, 1998). These neurons were first discovered in area F5 in macaques. In humans, the similar pattern of engagement of brain regions is seen within the corresponding Action Observation Network (AON) (Gallese et al., 1996; Rizzolatti et al., 1998; Grafton, 2009; Grèzes, Armony, Rowe, & Passingham, 2003; Jenkins, Brooks, Nixon, Frackowiak, & Passingham, 1994; Sakai, Ramnani, & Passingham, 2002). The brain areas that are part of this 40 AON include the inferior frontal gyrus pars opercularis (IFGo) and pars triangularis (IFGt), the Parietal Operculum (PO), the precentral gyrus (PCG), and supramarginal gyrus (anterior portion, SMGa, and posterior portion, SGMp) (Grafton, Arbib, Fadiga, & Rizzolatti, 1996; Grafton, 2009). The effectiveness of AOT, and its neural representation the AON, on motor recovery of upper extremity function has been studied with mixed results. While some clinical studies find AOT to be effective (Buccino & Riggio, 2006; Celnik et al., 2008; Ertelt et al., 2007, 2012; Franceschini et al., 2012), others have not (Cowles et al., 2012; Pomeroy, 2005). Such mixed results indicate, and we have emphasize before, that before clinical use of AOT can be widely advocated, there is a need for more basic understanding regarding the functional characterization of the behavior of the AON in individuals with stroke. Evidence from functional magnetic resonance imaging (fMRI) suggests cortical reorganization after stroke (Cacchio, De Blasis, De Blasis, Santilli, & Spacca, 2009; Carvalho, Teixeira, Lucas, Yuan, Chaves, Peressutti, Machado, Bittencourt, lez, et al., 2013). Specifically, activation of the AON during action observation for individuals with right upper extremity (UE) impairment shifts anteriorly in the inferior frontal gyrus (IFG) and is inversely correlated with functional ability scores (Figure 1) (Garrison et al., 2013). Rehabilitation of UE function may benefit from action observation and engagement of the AON to promote neural recovery, possibly driving neural plasticity. There is evidence suggesting that older adults create new motor memories, and possibly re-learn skilled motor movement (Buccino et al., 2004; Iacoboni et al., 1999). One form of learning, imitation, has a central role in human learning and development of motor and communicative skills (Iacoboni et al., 1999; Piaget, 1962; Tomasello, Savage-Rumbaugh, & Kruger, 1993). It is thought that the 41 most effective way to create motor memories is through imitation; pure observation or execution may not be as effective (Rossini et al., 2007). However, it is unclear which type of task is the most effective in engaging the AON for potential stroke rehabilitation. We will address this issue in our study. We ask, which condition (imitation, execution, or observation) engages the AON (inferior frontal gyrus, premotor cortices, inferior parietal lobule) to the highest degree? According to a study by Iacoboni, given that mirror neurons discharge more during the execution of an action than during its observation, and given that during imitation of an action, one simultaneously observes and performs that action, we could predict that the AON areas would show higher activity during imitation, reflecting the sum of the activity attributable to action observation and execution (Iacoboni & Dapretto, 2006; Iacoboni et al., 1999). These, and other, studies have shown increasing levels of AON engagement for healthy adults using fMRI in the following order: imitation > execution > observation. We predict a similar pattern will be seen in blood oxygen level dependent (BOLD) activity for individuals with chronic stroke affecting the upper extremity: imitation will yield the strongest AON activity, followed by the execution, and observation. Further understanding differing levels of AON engagement for different task conditions will allow us to investigate the basic neural underpinnings behind the AON activity, and such understanding may improve the development of new protocols for physical and occupational therapy. 42 METHODS Subjects This study included 42 individuals (22 participants with left hemisphere stroke and 20 non-disabled controls). In the stroke group ([S] n=22, 8 female), the average age was 59.1 ± 11.3 years old, average time since stroke 5 ± 3.8 years; all had mild-to-moderate lower extremity motor impairment. Individuals in the non-disabled group ([ND] n=20, 9 female) were matched to the stroke subjects in terms of age (65.5 ± 6.8 years) and gender. All individuals were right handed (prior to stroke), had normal or corrected-to-normal vision, and had no contraindications to undergo MRI. Inclusion criteria for individuals with stroke were chronic presentation (>3 months since stroke onset) of a single stroke, mild-to-moderate upper extremity impairment as determined by a Fugl-Meyer upper extremity assessment (FMA-UE), and no diagnosis of apraxia. Group characteristics are summarized in Table 1. Characteristics of participant with stroke are described in Table 2. Individuals in both groups were recruited through community centers, bulletin boards, and volunteer research organizations. All participants gave informed consent in accordance with Institutional Review Board approval guidelines approved by the University of Southern California. Functional Neuroimaging: fMRI fMRI Data Acquisition Scanning was completed on 3T Siemens Trio and Prisma MRI scanners at the University of Southern California Dornsife Neuroimaging Center. Anatomical images were acquired with a 43 T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) sequence (TR/TE=2350/3.09ms, 208 1-mm slices, 256x256 mm, flip angle 10°). Functional images were acquired with a T2*-weighted gradient echo sequence (repetition time [TR]/echo time [TE]=2000/30ms, 37 slices, voxel size 3.5 mm isotropic voxels, flip angle 90°). In addition, a resting state fMRI sequence was performed. A T2-weighted volume was acquired and, for the non-disabled group, reviewed by an independent neuroradiologist in compliance with the scanning center’s policy and local IRB guidelines. T2-weighted scans for the stroke group were not analyzed by the researchers for any purpose in this study. No participant data was removed from the study due to incidental findings. fMRI Tasks and Design Design. The fMRI paradigm consisted of a block design in which participants were exposed to three conditions: (1) observation of videos of left or right hand actions (OBSL, OBSR), (2) execution of left or right hand actions cued by still images of a left or right hand (EXEL, EXER), (3) imitation of left or right hand actions cued by videos of a left or right hand actions (IMIL, IMIR), (4) observation of a green circle on the left or right side of the screen in the same location as the hand in the still images or hand action videos (visual control), or (5) looking at a fixation cross (rest control). See Supplementary Figure 1 for experimental conditions. Stimuli. For the “action observation” conditions (OBSL, OBSR), videos depicted a mean- age-matched actor’s left or right hand moving his left or right index finger towards two buttons locate on the button-box device, presented to the subject in a first-person perspective. For the 44 “action execution” conditions (EXEL, EXER), a still image from the button-press video was captures and presented to the subject; this image depicted the hand in a neutral starting position and a red border cue indicating the direction of movement of the participant’s index finger. For the “action imitation” conditions (IMIL, IMIR), a cue of a large red border indicated to the participant to imitate the movement. The viewed actions were created to mimic the goal-oriented movement of pressing on a telephone number pad, utilizing index finger flexion and abduction and adduction of the finger towards a button to the left or right. The subjects performed the actions to the best of their capability. Participants were trained in a mock scanner to perform the appropriate action for each condition prior to the actual scan. Practice time varied depending on the participants’ understanding of the instructions and motor capability. Practice was only terminated when the participant felt comfortable with the instructions and execution of the task. In both the practice trial and the actual scanning, participants viewed stimuli via a mirror and a projection system. Each video or still image remained on the screen for four seconds for participants to observe, execute, and imitate. Each block consisted of seven conditions (OBSL, OBSR, EXEL, EXER, IMIL, IMIR, control). Each total block length was 12 seconds, each condition was repeated 4 times, and there were 20 trials/run per condition (including rest). The conditions were counterbalanced by run, and pseudo-randomized and repeated across four 6- minute functional runs. Participants also received a structural MPRAGE and functional resting state scan. Resting state data were not analyzed for the purpose of this study. Participants were instructed to remain still during scanning and were visually monitored for movement. If participants were required to imitate or execute, they were requested to only 45 move the hand from the wrist down and keep the rest of the body as still as possible. A blanket and back support was provided for comfort and stability of movement. A research associate was present in the scanner room at all times to keep the participant comfortable and ensure as little motion as possible. If any extraneous participant movement was detected by the research participant was verbally reminded between runs to remain as still as possible. To confirm that participants were paying attention to the conditions, each participant was asked questions about the videos at the end of each run (e.g., “In the last video you saw, which hand did the actor use?”). Behavioral Assessments Individuals with stroke were administered the Fugl-Meyer Upper Extremity Assessment (FMA-UE) (Fugl-Meyer, Jääskö, Leyman, Olsson, & Steglind, 1975; Sullivan et al., 2011) and the Wolf Motor Function Test (WMFT) (Wolf et al., 2001) to assess upper extremity motor function, balance, sensation, and joint function. The FMA-UE exam was conducted and scored by a certified, trained, and blinded Occupational Therapist (OT) with no other involvement of the study. For each component of the FMA-UE, the score ranged from 0 = none to 2 = full, for a maximum score of 66. For the purposes of our study, we included motor components of reflexes, dynamic movement within flexor synergy, movement mixing flexion and extension synergies, movements with little or no synergy dependence, normal reflex activity, wrist stability and movement, hand, and coordination/speed. Individuals were also assessed with the Wolf Motor Function Test to test for function of the upper extremity in the motor domain. The Wolf Motor Function Test (WMFT) was 46 conducted by the same OT or by a certified and trained researcher, when necessary. Performance on the WMFT was videotaped and scored by a trained, blinded researcher for movement time(s) and functional ability scale (FAS) score. WMFT actions included goal- oriented movements, such as picking up a pencil, picking up a paperclip, stacking checkers, and flipping cards, for the paretic and non-paretic arm. FAS score ranged from 0-5, where 0 = does not attempt movement and 5 = movement is normal, for a score of 20 per arm. Here, we present FAS scores for the affected arm. fMRI Analysis Preprocessing, Individual and Group Analyses Preprocessing Functional neuroimaging data analysis was carried out using FEAT (FMRI Expert Analysis Tool) Version 6.00, part of FSL (FMRIB's Software Library, www.fmrib.ox.ac.uk/fsl). The following preprocessing steps were applied: first level skull stripping of the anatomical image for registration using automated BET procedure (Smith, 2002); registration to high-resolution structural and, then, standard MNI space images through FLIRT (Jenkinson, Bannister, Brady, & Smith, 2002; Jenkinson & Smith, 2001), manual checking of the skull stripping by the researcher; motion correction using MCFLIRT (Jenkinson et al., 2002); additional motion correction using ICA-AROMA (Pruim, Mennes, van Rooij, et al., 2015; Pruim, Mennes, Buitelaar, & Beckmann, 2015); automated non-brain removal of the fMRI data using BET (Smith, 2002); spatial smoothing using a Gaussian kernel of 5mm FWHM; and high-pass temporal filtering using double gamma hemodynamic response function (HRF). 47 Individual and Group Analyses For each subject, a time-series statistical analysis of each run (fixed effects) was carried out using FILM GLM with local autocorrelation correction (Woolrich, Ripley, Brady, & Smith, 2001). These Z (Gaussianised T/F) statistic images were then thresholded using clusters determined by Z>2.3 and a (Bonferroni corrected) cluster significance threshold of P=0.05 (Worsley, 2001). A second level analysis for each subject was conducted, grand-mean scaling of the entire 4D dataset by a single scaling factor averaged across the maximum four runs, and carried out using a fixed effects model by forcing the random effects variance to zero in FLAME (FMRIB’s Local Analysis of Mixed Effects; Beckmann, Jenkinson, & Smith, 2003; Woolrich, 2008; Woolrich, Behrens, Beckmann, Jenkinson, & Smith, 2004). At the group-level, analyses were completed using a mixed effects model that included both fixed effects and random effects from cross session/subject variance in FLAME. Again, Z (Gaussianised T/F) statistic images were then thresholded using clusters determined by Z>2.3 and a (Bonferroni corrected) cluster significance threshold of p=.05. Region of Interest Analysis A priori regions of interest (ROI) were the following regions of the human AON: inferior frontal gyrus pars opercularis (IFGo) and pars triangularis (IFGt), the parietal operculum (PO), the precentral gyrus (PCG), and supramarginal gyrus (anterior portion, SMGa and posterior portion, SMGp) for both the left and right hemispheres (Caspers, Zilles, Laird, & Eickhoff, 2010; Cross, Kraemer, Hamilton, Kelley, & Grafton, 2009; Scott T Grafton, 2009a; Small, Buccino, & 48 Solodkin, 2012). All ROIs were defined anatomically using the Harvard-Oxford atlas, with probabilistic threshold of greater than 50% applied for each ROI. Mean percent signal change (% SC) within each ROI was extracted for each task condition and each participant using Featquery in FSL. Student’s un-paired t-test was calculated within a ROI to assess for significant %SC difference between groups (ND, S) for contrasts of action execution-observation and action imitation-execution. Since we hypothesize that imitation > execution > observation, we extrapolate that %SC of imitation – execution will be greater than execution – observation. Brain Behavior Analysis For each left and right hemisphere AON ROI (IFGo, IFGt, PCG, SMGa, SMGt), Spearman’s rho correlations were tested for individuals with stroke between ROI activity and motor scores for the FMA-UE. Separate analyses were conducted for the WOLF. Lesion Analysis Lesions were drawn semi-manually by a trained research assistant following a detailed lesion tracing protocol (Riley et al. 2011) using MRIcron (Rorden and Brett 2000). Semi- automated Robust Quantification of Lesions (SQRL) Toolbox was also developed and used for assessment of automated and manual lesion quantification (Ito, Anglin, & Liew, 2017). Lesion masks were then smoothed using a 2mm Gaussian kernel. For each subject, a small control mask was manually created in healthy white matter tissue of the contralesional hemisphere for comparison and control analysis purposes. The white matter mask was used to determine the mean and standard deviation of healthy white matter voxel intensities within each subject’s 49 anatomical image using fslstats. Each subject’s anatomical image was then thresholded at one standard deviation away from the mean white matter intensity, such that voxels with a signal intensity within or above the normal range would be excluded from the final lesion mask. Finally, the volume of the lesion was calculated using fslstats. Lesion location for individuals with stroke is presented in Figure 2. Percent of Lesion Overlap with ROIs To examine the percent of lesion overlap with each ROI, each individual’s binary lesion map was normalized to standard space. Each normalized lesion map was then masked with each ROI using fslmaths. The number of voxels in the overlapping area was obtained using the fslstats. The number of voxels in the overlapping area was then divided by the total number of voxels within the ROI to calculate the percent of overlap between the lesion and the ROI for each subject. RESULTS In this study, we examined the AON for the upper extremity (UE) in non-disabled adults and individuals with stroke. We conducted main effect and BOLD percent signal change analyses in regions of interest (ROIs) of the AON for each contrast- rest (Figure 3) as well as contrasts of execution – observation and imitation – execution (Figure 4). All analyses were conducted for both groups. 50 Whole brain fMRI Results Main effect of Observation, Execution, Imitation Main effect analysis of each contrast – rest was conducted to ensure AON engagement. Results show that during left upper extremity, or hand, action observation in the non- disabled group (ND), significant activity was found in the bilateral AON, including bilateral PCG, left SMG, and right IFG. During left (corresponding to non-paretic) upper extremity action observation in individuals with stroke group (S), significant activity was found in the same regions, with more pronounced activity in the right IFG (Figure 3). For the right (paretic) hand, ND engages the bilateral PCG and bilateral SMG, whereas S engages bilateral PCG, bilateral SMG, and right IFG. One difference between the two groups is the engagement of the right IFG for the stroke group during observation of both right and left hand actions. During left hand action execution in ND, significant activity was found in the AON, including the bilateral PCG, bilateral SMG, and right IFG. In the S group, significant activity was found in the same regions, yet also in the bilateral IFG. During right (paretic) hand action execution, ND and S engage bilateral PCG, SMG, and right IFG. A difference between these two groups again seems to the be the IFG, where the stroke group has more activity. Interestingly, for execution (of the paretic hand), activity is located on the right hemisphere even for right hand actions. During left hand action imitation in ND, significant activity was found in the AON, including bilateral PCG, bilateral SMG, and a bit of right IFG. In the S group, significant activity was found in the bilateral AON, including bilateral PCG, bilateral SMG, and bilateral IFG. During right (paretic) hand action imitation, significant activity was found in ND engages the AON, 51 including bilateral PCG, left SMG, and right IFG. In the S group, significant activity was found in the AON, including bilateral PCG, bilateral SMG, and right IFG. Again, during imitation, a difference between these groups is in the level of engagement of the IFG; the S group has more activity in the IFG. Also, again, for imitation of the right paretic hand, the activity is located on the right hemisphere (Figure 3). Main effect of Action Execution – Observation In order to understand the relationship between contrasts, an analysis of subtraction between contrasts was conducted. During left upper extremity action execution – observation (EXEL-OBSL) in the non- disabled group (ND), significant activity was found in the bilateral AON, including bilateral IFG, bilateral SMG anterior division, and bilateral PCG (Table 3, Figure 4). During left (corresponding to non-paretic) upper extremity action execution – observation (EXEL-OBSL) in individuals with stroke group (S), significant activity was found in the bilateral AON, including bilateral IFG opercularis, bilateral SMG posterior and anterior division, and bilateral PCG (Table 3, Figure 4). During right upper extremity action execution – observation (EXER-OBSR) in the non-disabled group (ND), significant activity was found in the bilateral AON, including bilateral inferior IFG opercularis, right IFG triangularis, bilateral SMG anterior division, and bilateral PCG (Table 3, Figure 4). The only task by hand contrast that differed was during right (corresponding to paretic) upper extremity action execution – observation (EXER-OBSR) in individuals with stroke group (S). 52 Here, significant activity was found in the right AON instead of bilateral AON. These regions included the right IFG opercularis, and the right SMG anterior division (Table 3, Figure 4). Main effect of Action Imitation – Execution During left upper extremity action imitation – execution (IMIL-EXEL) for ND, significant activity was found in one region of the AON, the left PCG (Table 4, Figure 4). During left (corresponding to non-paretic) upper extremity action imitation – execution (IMIL-EXEL) for S, significant activity was found in the AON, including left IFG opercularis, bilateral PCG, and right SMG posterior division (Table 4, Figure 4). During right upper extremity action imitation – execution (IMIR-EXER) for ND, significant activity was found in one AON region of right SMG anterior (Table 4, Figure 4). During right (corresponding to paretic) upper extremity action imitation – execution (IMIR-OBSR) for S, significant activity was found in one AON region of bilateral SMG posterior (Table 4, Figure 4). In this main effect analysis, there appears to be activity in more regions of the AON in IMIL-EXEL in S (bilateral PCG, bilateral SMG posterior, and left IFG opercularis) than ND (left PCG). For IMIR-EXER, both groups engage the SMG, however, ND engages right SMG and S engages bilateral SMG posterior. Region of Interest Percent BOLD Signal Change Results Percent BOLD Signal Change (%SC) for the AON ROIs of IFG opercularis, IFG triangularis, PCG, SMG anterior, and SMG posterior portion for the left and right hemispheres were calculated through FSL featquery. Paired t-test was used to compare %SC between contrasts of 53 EXE-OBS and IMI-EXE for each hand (Table 5). Further comparisons between contrasts for each ROI was conducted to see which, if any, ROIs follow a pattern where imitation>execution>observation. In ND, we find statistically significant %SC for left UE during EXE-OBS and IMI-EXE in the bilateral AON, including bilateral IFGo, right PCG, bilateral SMGa and SMGp. For the right UE, we find significant %SC for bilateral IFGo and bilateral SMGa and SMGp, however, not PCG (Table 5). In S, we find statistically significant %SC for left UE during EXE-OBS and IMI-EXE in parts of the AON: the right IFGo, left IFGt, right PCG, bilateral SMGa and left SMGp. There are no significant %SC for the right UE, corresponding to the paretic hand (Table 5). Our hypothesis of imi>exe>obs was accepted for the ND group in the bilateral PCG for left and hand and right SMGa for the right hand. This pattern existed in more AON regions for the S group: for the left hand, in the left IFGo, right IFGt, bilateral SMG and for the right (paretic) hand in the bilateral IFGo, and right PCG. Such analyses suggest that imitation engages the AON the most in the IFGo for the stroke group for the paretic hand. Brain Behavior Analyses Fugl-Meyer Assessment As expected, FMA scores correlate with activity of the right (paretic) hand. FMA-UE scores in the stroke group significantly correlate with ROI activity in the bilateral IFG, bilateral SMG, and left IFGt and PCG during right (paretic) execution. Activity during left imitation – execution was present in the right IFGo only. Specific correlations are described below. 54 Specifically, FMA-UE scores in the stroke group significantly correlate with ROI activity in the: IFGo_L during right action execution (EXER-rest, r= .449, p=.036) and right action execution minus observation (EXER-OBSR, r=.475, p=.025); IFGo_R during right action execution (EXER- rest, r=.4656, p=.029) and left action imitation – execution (IMIL-EXEL, r=.488, p=.021); IFGt_L during right action execution (EXER-rest, r=.559, p=.007) and right action execution – observation (EXER-OBSR, r=.568, p=.006); IFGt_R for right action execution (EXER-rest, r=.464, p=.03) and right action execution – observation (EXER-OBSR, r=.456, p=.033); PCG_L for right action execution (EXER-rest, r=.510, p=.015) and action right execution – observation (EXER- OBSR, r=.526, r=.012); SMGa_R for right action execution (EXER-rest, r=.529, p=.011) and right action execution – observation (EXER-OBSR, r=.529, p= .011), SMGa_L for right action execution (EXER-rest, r=.582, p=.004) and right action execution – observation (IMIL-EXEL, r=.552, p=.008); SMGp_L for right action execution (EXER-rest, r=.542, p=.009) and right action execution – observation (EXER-OBSR, r=.524, p=.012); and SMGp_R for right action execution (EXER-rest, r=.522, p=.013) and right action execution – observation (EXER-OBSR, r=.602, p=.003). Wolf Motor Function Test Also as expected, WMFT scores correlate with activity for the right (paretic) hand. WMFT scores in the stroke group significantly correlate with ROI activity in the bilateral IFG, bilateral SMG, and left PCG for right (paretic) execution, and left IFGt for right observation. Activity for left hand execution was found in the right IFGt only. Specific correlations are described below. 55 Specifically, WMFT scores in the stroke group significantly correlate with ROI activity in the: IFGo_L for right action execution (EXER-rest, r=.592, p=.005) and right action execution – observation (EXER-OBSR, r=.625, p=.002); IFGo_R for right action execution (EXER-rest, r=.486, p=.026); IFGt_L for right observation (OBSR-rest, r=-.588, p=.005), right action execution (EXER- rest, r=.633, p=.002), right action execution – observation (EXER-OBSR, r=.680, p <.001); IFGt_R for left action execution (EXEL-rest, r=.531, p=.034), right action execution (EXER-rest, r=.531, p=.013), left execution – observation (EXEL-OBSL, r=.453, p=.039), and right action execution – observation (EXER-OBSR, r=.485, p=.026); PCG_L for right action execution (EXER-rest, r=.601, p=.004) and right action execution – observation (EXER-OBSR, r=.633, p=.002); SMGa_R for right action execution (EXER-rest, r=.587, p=.005) and right action execution – observation (EXER- OBSR, r=.638, p=.002); SMGa_L for right action execution (EXER-rest, r=.561, p=.008) and right action execution – observation (EXER-OBSR, r=.603, p=.004); SMGp_L for right action execution (EXER-rest, r=.535, p=.013) and right execution – observation (EXER-OBSR, r=.572, p=.007); and SMGp_R for right execution (EXER-rest, r=.548, p=.01) and right execution – observation (EXER- OBSR, r=.691, p<.001). DISCUSSION We examined brain activity of the AON by contrasting action imitation, execution, and observation in non-disabled adults and individuals with stroke affecting the upper extremity (UE). First, we found activity in the AON for each of our contrasts- rest, which confirmed that our experiment engaged the AON for both groups. This supports our hypothesis that the AON is engaged in both non-disabled and individuals with stroke during a button-press task. 56 The main effect analyses for the comparison of execution – observation of the left hand, shows bilateral AON activity in both the non-disabled and stroke groups; for the right hand, it shows activity in the bilateral AON for the non-disabled and activity in the right AON for the stroke group. For main effect analyses, during imitation – execution of the left hand, we found activity in the AON for both the non-disabled and individuals with stroke group; for the right hand, we found activity in the one AON ROI (the supramarginal gyrus) for the non-disabled group and one AON ROI (right supramarginal gyrus) activity in the stroke group. These results suggested that there is more bilateral AON recruitment for non-disabled individuals, yet there appears to be unilateral (ipsilesional) recruitment for individuals with stroke for the right (disabled) hand. Evidence from other groups suggest greater activity in the ipsilesional hemisphere after stroke promotes recovery of motor function (Grefkes et al., 2008; Marshall et al., 2000; Nudo, 2006; Richards, Stewart, Woodbury, Senesac, & Cauraugh, 2008; Ward & Cohen, 2004). This ipsilesional activity may be seen in our group of individuals with stroke affecting the upper extremity. For the percent signal change in ROI activity, we hypothesized that activity of imitation would be greater than activity of execution, and execution would be greater than observation. We found that for the left hand, execution > observation for non-disabled in right IFGo, bilateral PCG, and bilateral SMG in non-disabled; and for stroke in bilateral IFGo, left IFGt, right PCG, bilateral SMGa, and right SMGp. The activity for imitation > execution was not found to be significant for any ROI, however, a trend of imitation>exection>observation was found in the stroke group for the IFG. Interestingly, it is believed that imitation recruits additional brain regions than execution or observation alone (Rossini et al., 2007) and that there is a significant 57 difference in greater signal intensity for imitation than execution or observation alone (Iacoboni et al., 1999). We find a similar pattern in the IFG for our stroke group, suggesting that this region is most utilized for actions involving imitation. Our curiosity made us wonder if reverse contrasts would show additional results. This speculation was tested in a post-hoc contrast of execution-imitation and results indicated that, in stroke, there is greater activity in the right supramarginal gyrus for execution-imitation than imitation-execution. We speculate that, perhaps, in a stroke group execution recruits more brain regions in conducting the movement. Such post-hoc analyses suggest that perhaps regions of the AON do not all function in synchrony. Perhaps where the IFG is engaged the most during imitation, the SMG is engaged the most during action execution. Additional analyses will need to be conducted before claims on directionality of activity can be made. LIMITATIONS & FUTURE DIRECTIONS We acknowledge that there may be limitations of this study, beginning with the participants in our stroke group. In regards to sample size, while previous research has found modest AON activity effects for group samples of n=12 individuals with stroke (Garrison et al., 2013), power analysis suggests a larger sample size is necessary for an appropriate effect size. Replication of this work in a larger sample would improve our understanding of how the current findings relate to individuals after stroke. Heterogeneity of our stroke population due to different lesion location and variability in lesion type, size, and vasculature affected also cause additional variance in the data. While such heterogeneity is common in the stroke population at large, studies with multiple variables are difficult to interpret, at best. Our attempts to 58 disentangle the results of this study are prominent, yet, homogeneous group populations make for stronger claims. Future work of the AON representation of the UE for skilled or learned movement is still necessary. Examples of questions still to be asked include (1) questions of laterality and dominant hemisphere post-stroke, (2) determining how additional sequences, such as resting state scans or diffusion tensor imaging (DTI), provide further information regarding intrinsic connectivity of brain networks post stroke, and (3) distinguishing differences between effectors for AON engagement (hand versus foot). Additional types of analyses, specifically questions regarding analyses differences between main effect versus ROI percent signal change should also be considered. A formal laterality index study of the current work would be needed to quantify hemispheric activity. Additional analyses using masked ROIs or functional localizers could help elucidate differences between types of analyses. In addition to research on the task-based activity of the AON, future studies may also ask questions about resting state fMRI and AON activity after stroke. Such multifaceted research on the AON will allow us to understand changes in the neural circuitry post stroke. With this understanding, we can begin to determine what types of conditions engage the AON and, potentially, determine what types of tasks are clinically useful for AOT. CONCLUSION This study supports our hypothesis that activity within the AON differs among conditions of action observation, imitation, and execution in individuals with stroke; however, the direction of that activity (imitation > execution > observation) still remains in question. 59 While the clinical implications of our findings (IFG is engaged the most during imitation, SMG is engaged the most during execution) remain to be explored, it does support the notion that engagement of ROIs within the AON is condition specific. These results provide additional evidence in understanding how the AON is engaged for individuals with stroke. Understanding of the engagement and functional activity of the AON, and individual differences in this activity, may allow us to develop rehabilitation protocols for patients after stroke. Personalization of rehabilitative protocols may, for example, show that one individual engages the AON most during the imitation condition or the execution condition, but not both, suggesting that one condition is best method for that individual’s recovery. Development of clinical and interventional studies incorporating AON engagement during therapies of UE post- stroke rehabilitation would be a necessary future step on this path. 60 Figure 2.1. Main effect of action observation (adapted from Garrison et al 2013). Brain regions of the AON are engaged during action observation for participants with stroke (red), non- disabled individuals (blue), and overlap between groups (purple). Shown at p<0.01, uncorrected. 61 Figure 2.2 Lesion Masks of Individuals with Stroke. Semi-manual drawn masks of lesions of 3 individuals with stroke are presented. Lesions are depicted in yellow in the coronal and axial views of three study participants. As is depicted through the different sizes and locations of the yellow lesion mask, there is variety in the study participants’ lesion size and location, resulting in differences in behavioral measures. 62 Figure 2.3. Whole brain activity during left and right hand observation, execution, and imitation for non-disabled and individuals with stroke. Top: Observation – rest, Middle: Execution – rest, Bottom: Imitation – rest. Nondisabled individuals are represented in blue. Individuals with stroke are represented in red. Overlap between groups is represented in purple. Z=2.3, corrected for multiple comparisons. 63 Figure 2.4 Whole brain activity during left and right hand subtraction contrasts. Hypothesis suggests Imitation>Execution>Observation, thus, subtraction contrasts between these conditions are presented. Top: Action Execution – Observation, Bottom: Action Execution - Observation. Nondisabled individuals are represented in blue. Individuals with stroke are represented in red. Overlap between groups is represented in purple. Z=2.3, corrected for multiple comparisons. 64 Figure 2.5. (Supplementary) Stimuli for fMRI study of the AON for Upper Extremity. The fMRI paradigm was a block design in which participants (a) observe videos of left or right hand actions (OBSL, OBSR), (b) execute from a cue on still images of a left or right hand (EXEL, EXER), (c) imitate from a cue on a video of a left or right hand (IMIL, IMIR), (d) observed a green ball (control), or (e) observed a fixation cross (rest). Actions required eversion and inversion of the index finger towards buttons on a button box, to the best of the participant’s capability. 65 Table 2.1. Demographics of Stroke (S) and Non-Disabled (ND) groups. The study involved 42 total individuals (n=22 Stroke, n=20 ND). Demographics of participants are presented. 66 Table 2.2 Demographics and Lesion Information of Stroke (S) group. Participants with stroke demographics and lesion information are presented. Sub-groups included type of stroke (ischemic or hemorrhagic), Vasculature (Middle Cerebral Artery, Anterior Cerebral Artery, Basilar Artery), Lesioned Vascular Territory (Internal Capsule, Internal Capsule + Cortex, Non- Internal Capsule). Behavioral assessment score of the Fugl-Meyer Assessment for the Upper Extremity and Wolf Motor Function Test (Functional Ability Score) is also presented. L = Left, MCA = Middle Cerebral Artery, ACA = Anterior Cerebral Artery, IC = Internal Capsule, IC+ = Internal Capsule + Cortex, Non-IC = Non-Internal Capsule, FMA-UE = Fugl Meyer- Assessment Upper Extremity, WMFT (FAS) = Wolf Motor Function Test (Functional Ability Score) 67 Table 2.3. Main effect contrast of execution – observation for left and right hand actions. Peak activations during left and right hand execution minus observation contrast action for non-disabled participants and participants with stroke. 68 Table 2.4. Main effect contrast of imitation – execution for left and right hand actions. Peak activations during left and right hand imitation minus execution contrast action for non- disabled participants and participants with stroke. 69 Table 2.5. Percent BOLD Signal Change within ROI. Percent BOLD Signal Change (%SC) for the AON ROIs of inferior frontal gyrus pars opercularis (IFGo), inferior frontal gyrus, pars triangularis (IFGt), precentral gyrus (PCG), supramarginal gyrus anterior portion (SMGa), and supramarginal gyrus posterior (SMGp) portion for the left and right hemispheres. 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Statistical Analysis of Activation Images. Retrieved from https://pdfs.semanticscholar.org/0b27/ffcba6e006f86c7e52fce4cc853af9405329.pdf 80 CHAPTER THREE: ENGAGEMENT OF THE ACTION OBSERVATION NETWORK FOR LOWER EXTREMITY ACTIONS IN INDIVIDUALS WITH STROKE INTRODUCTION Stroke is the largest contributor to disability in the U.S. and worldwide, often resulting in physical impairments of hemiplegia or weakness of the affected upper (UE) and/or lower (LE) extremities (Duncan, Goldstein, Matchar, Divine, & Feussner, 1992; Kochanek SL; Xu JQ, Arias E., 2014; Mozaffarian et al., 2016). Improved functional recovery of the motor deficits associated with stroke have been demonstrated with participation in neurorehabilitative physical and occupational therapy (Carvalho et al., 2013; Chen & Winstein, 2009; Darling, Pizzementi, & Morecraft, 2011; Pekna, Pekny, & Nilsson, 2012; Wolf, Winstein, Miller, Taub, & Uswatte, 2006). Often, forms of neurorehabilitative therapy involve repetitive, skilled or goal- oriented movements of the paretic limb in order to induce positive neuroplasticity (Ertelt et al., 2007; Grefkes & Fink, 2011; Rossetti, Rode, & Goldenberg, 2005). Such methods are supported by the motor learning theory; in particular, empirical evidence that supports specificity, repetition, and salience of movements to increase neural plasticity (Kleim et al., 2002; Kleim & Jones, 2008). However, these forms of physical and occupational therapy may not be feasible for individuals with severe motor impairments or individuals in the chronic stage of stroke (post three months of stroke) where they are receiving little to no supervised physical or occupational therapy (Feigenson, 1981; Jongbloed & Wendland, 2002; Maulden, Gassaway, Horn, Smout, & DeJong, 2005). To address these partictular challenges, other forms of therapy 81 that are accessible and cost-effective to these individuals are needed; therefore, alternative strategies have been proposed. One such treatment technique relies upon the recruitment of the motor network without explicit motor practice. Increasing evidence indicates that the same motor regions of the brain that are engaged during execution of actions may also be involved during observation of those same actions. Activating these motor brain networks through what is called ‘action observation therapy’ (AOT) may allow for individuals with severe impairment, who cannot perform tasks due to physical limitations, or those in the chronic stage of recovery, who have less access to therapy, to engage the motor network and improve neurorehabilitation. The neural basis for AOT is thought to involve the mirror neuron system. Mirror neurons, first discovered in area F5 of the macaque brain, discharge during performance of an action as well as during observation of another person performing the same or similar actions (di Pellegrino, Fadiga, Fogassi, Gallese, & Rizzolatti, 1992; Gallese, Fadiga, Fogassi, & Rizzolatti, 1996; Rizzolatti, Luppino, & Matelli, 1998). In humans, there is evidence for a similar pattern of engagement of motor brain regions for action observation and action execution (Fadiga, Fogassi, Pavesi, & Rizzolatti, 1995; Gallese et al., 1996; Rizzolatti & Craighero, 2004; Rizzolatti et al., 1998), as well as involvement in imitative learning (Buccino et al., 2004; Iacoboni et al., 1999). This has been termed the Action Observation Network (AON) (Gallese et al., 1996; Rizzolatti et al., 1998; Grafton, 2009; Grèzes, Armony, Rowe, & Passingham, 2003; Jenkins, Brooks, Nixon, Frackowiak, & Passingham, 1994; Sakai, Ramnani, & Passingham, 2002). The brain regions that are part of the AON include the inferior frontal gyrus pars opercularis (IFGo) and pars triangularis (IFGt), the Parietal Operculum (PO), the precentral gyrus (PCG), and 82 supramarginal gyrus (anterior portion, SMGa and posterior portion, SGMp) (Grafton, 2009). Thus, the AON may potentially support action observation activating motor brain regions, thus making AOT a potentially useful form or supplement for physical and occupational therapy post-stroke. effective. The effectiveness of AOT, and its corresponding neural representation AON, on motor recovery of upper extremity function has been studied with mixed results. While some clinical studies find support for AOT (Giovanni Buccino & Riggio, 2006; Celnik, Webster, Glasser, & Cohen, 2008; Ertelt et al., 2007; Ertelt, Hemmelmann, Dettmers, Ziegler, & Binkofski, 2012; Franceschini et al., 2012), some have not (Cowles et al., 2012; Pomeroy, 2005). Such mixed results indicate, and we emphasize, that before clinical applications of AOT can be effectively used, there exists a need for more basic science research regarding activation of the AON in individuals with stroke. Evidence from functional magnetic resonance imaging (fMRI) studies demonstrate cortical reorganization after stroke (Cacchio, De Blasis, De Blasis, Santilli, & Spacca, 2009; Carvalho et al., 2013). Specifically, the representation of the AON during action observation for individuals with right upper extremity impairment shifts anteriorly in the inferior frontal gyrus (IFG) and is inversely correlated with functional ability scores (Garrison, Aziz-Zadeh, Wong, Liew, & Winstein, 2013). At the current time, the body of evidence supporting AOT is inconclusive, but known investigations have focused on upper extremity recovery (Giovanni Buccino & Riggio, 2006; Celnik et al., 2008; Ertelt et al., 2007, 2012; Franceschini et al., 2012). However, similar research for the representation of the AON and use of AOT for lower extremity (LE), or foot, actions after stroke is limited, even though strokes often involve 83 impairment to the legs and feet (Burke, Dobkin, Noser, Enney, & Cramer, 2014; Enzinger et al., 2008; Tang et al., 2010). Previous work indicated BOLD (Blood Oxygen Level Dependent) activity for foot actions during observation in the premotor and supplementary motor areas (Buccino et al., 2001) as well as the posterior parietal lobule (Small, Buccino, & Solodkin, 2012). In complement to such studies, representation for the skilled lower extremity movements that utilize cortical activity, can be further investigated for non-disabled and individuals with stroke. The present study aims to address this gap in knowledge. This study was designed to improve our understanding of AON engagement, as measured by fMRI BOLD activity, for goal-oriented actions involving the lower extremity (i.e. foot and ankle movements). Here, we ask, what is the representation of the AON for Lower Extremity (LE), or foot, in Non-Disabled (ND) adults and individuals with stroke (S)? We predict that neural activity within the AON will exist for during conditions of action execution and action observation. This activity will be present for both ND and S groups in the whole brain analyses for AON, but with varying percent signal change for each region of interest. We predict correlations between behavioral assessments and brain activity within the AON, where individuals with higher impairment will recruit the AON to a greater degree. Further understanding the AON’s representation for the LE may be useful in developing or supplementing protocols of physical and occupational therapy for individuals with stroke affecting the LE. 84 METHODS Subjects The study included 28 individuals (16 participants with left hemisphere stroke and 12 non-disabled controls). In the stroke group ([S] n=16, 5 female), the average age was 64.4 ± 10.3 years old, average time since stroke was 4 ± 3.5 years, and all had mild-to-moderate lower extremity motor impairments. Individuals in the non-disabled group ([ND] n=12, 6 female) were matched to the stroke group in terms of age (61.7 ± 11.3 years) and gender stratification. All individuals were right handed (prior to stroke), had normal or corrected-to-normal vision, and were safe for MRI. Additional inclusion criteria for individuals with stroke were chronic presentation (>3 months since stroke onset), with no prior history of stroke, mild-to-moderate lower extremity impairment as determined by a Fugl-Meyer lower extremity assesement, and no diagnosis of apraxia. For all participants, mean age (including non-disabled controls) was 63.2 ± 10.8 years. Group characteristics are summarized in Table 1. Characteristics of participant with stroke are described in Table 2. Individuals in both groups were recruited through community centers, bulletin boards, and volunteer research organizations. All participants gave informed consent in accordance with Institutional Review Board approval guidelines approved by the University of Southern California. 85 Functional Neuroimaging: fMRI fMRI Data Acquisition All scanning was completed on a 3T Siemens Trio MRI scanner at the University of Southern California Dornsife Cognitive Neuroimaging Center. Anatomical images were acquired with a T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) sequence (TR/TE=2350/3.09ms, 208 1-mm slices, 256x256 mm, flip angle 10°). Functional images were acquired with a T2*-weighted gradient echo sequence (repetition time [TR]/echo time [TE]=2000/30ms, 37 slices, voxel size 3.5 mm isotropic voxels, flip angle 90°). In addition, a resting state fMRI sequence was performed. A T2-weighted volume was acquired for blind review by an independent neuroradiologist in compliance with the scanning center’s policy and local IRB guidelines. T2-weighted scans were not analyzed by the researchers for any purpose in this study. No participant data was removed from the study due to incidental findings. fMRI Tasks and Design Design. The fMRI paradigm consisted of a block design in which participants were exposed to three conditions: (1) observe videos of left or right foot actions (OBSL, OBSR), (2) execute left or right foot actions when cued with still images of a left or right foot (EXEL, EXER), (3) imitate left or right foot actions when cued with videos of a left or right foot (IMIL, IMIR), (4) observe a green circle on the left or right of the screen in the same location as the foot in the still images and videos (visual control), or (5) look at a fixation cross (rest control). See Figure 1 for experimental conditions. 86 Stimuli. For the “action observation” conditions (OBSL, OBSR), videos depicted a mean- age-matched actor’s left or right foot moving towards two rectangles placed on the ground, presented in the first-person perspective. For the “action execution” conditions (EXEL, EXER), a still image from the video is presented with feet in a neutral starting position and a cue for execution. This cue is a red rectangle highlighting one of the two rectangles placed on the ground and indicates the direction of movement of the participant’s foot. For the “action imitation” conditions (IMIL, IMIR), a cue of a large red border was placed around the same video depicting an actor’s moving foot; the participant imitated the movement. The viewed actions were created to mimic the goal-oriented movement of pressing on a pedal during driving, utilizing plantar flexion and inversion or eversion of the foot, with the heel placed on the ground, towards a rectangle to the left or right. The subjects performed the actions to the best of their capability. Participants were trained to perform the appropriate action for each condition and first practiced the procedure in a mock scanner. Practice time varied depending on the participants’ understanding of the instructions and motor capability. Participants were able to practice until they felt comfortable with the instructions and tasks. Participants viewed stimuli via a mirror and a projection system. Each video or still image remained on the projected screen for participants to observe, execute, and imitate, for four seconds. Each block consisted of seven conditions (OBSL, OBSR, EXEL, EXER, IMIL, IMIR, control). Each total block length was 12 seconds, each condition was repeated 4 times, and there were 20 trials/run per condition (including rest). The conditions counterbalanced by run, and were pseudo-randomized and repeated across four 6-minute functional runs. Participants 87 also received a structural MPRAGE and functional resting state scan. Resting state data were not analyzed for the purpose of this study. Participants were instructed to remain still during scanning and were visually monitored for movement. If participants were required to imitate or execute, they were requested to only move the foot from the ankle and keep the rest of the body as still as possible. A blanket and back support was provided for comfort and stability of movement. A research associate was present in the scanner room to keep the participant comfortable and ensure as little motion as possible. If any extraneous participant movement was seen by the research assistant, this information was provided to the researcher conducting the scan, and the participant was verbally reminded between runs to remain as still as possible. To confirm that participants were paying attention to the conditions, each participant was asked questions about the videos at the end of each run (e.g., “In the last video you saw, which foot did the actor use?”). Behavioral Assessments Individuals with stroke were administered the Fugl-Meyer Assessment Lower Extremity (FMA-LE) (Fugl-Meyer, Jääskö, Leyman, Olsson, & Steglind, 1975; Sullivan et al., 2011) to assess for lower extremity motor function, balance, sensation, and joint function in hemiplegic patients. This exam was conducted and scored by an independent blind examiner who is qualified to give the exam and is a certified occupational therapist (OT), with no other involvement of the study. For each item of the FMA-LE, the possible score ranges from 0 = none to 2 = full, for a maximum possible score of 86. For the purposes of our study, we included 88 Lower Extremity Motor and Coordination/Speed (FMA-LE sections E & F), for a maximum score adjusted score of 34. FMA-LE Assessment is described in Supplemental Figure 1. fMRI Analysis Preprocessing Functional neuroimaging data analysis was carried out using FEAT (FMRI Expert Analysis Tool) Version 6.00, part of FSL (FMRIB's Software Library, www.fmrib.ox.ac.uk/fsl). The following preprocessing steps were applied: first level skull stripping of the anatomical image for registration using automated BET procedure (Smith, 2002); registration to high-resolution structural and/or standard MNI space images through FLIRT (Jenkinson, Bannister, Brady, & Smith, 2002; Jenkinson & Smith, 2001), manual checking of the skull stripping by the researcher; motion correction using MCFLIRT (Jenkinson et al., 2002); additional motion correction using ICA-AROMA (Pruim, Mennes, van Rooij, et al., 2015; Pruim, Mennes, Buitelaar, & Beckmann, 2015); automated non-brain removal of the fMRI data using BET (Smith, 2002); spatial smoothing using a Gaussian kernel of 5mm FWHM; and high-pass temporal filtering using double gamma hemodynamic response function (HRF). Individual and Group Analyses For each subject, a time-series statistical analysis of each run (fixed effects) was carried out using FILM GLM with local autocorrelation correction (Woolrich, Ripley, Brady, & Smith, 2001). These Z (Gaussianised T/F) statistic images were then thresholded using clusters determined by Z>2.3 and a (Bonferroni corrected) cluster significance threshold of P=0.05 89 (Worsley, 2001). A second level analysis for each subject was conducted, grand-mean scaling of the entire 4D dataset by a single scaling factor averaged across the maximum four runs, and carried out using a fixed effects model by forcing the random effects variance to zero in FLAME (FMRIB’s Local Analysis of Mixed Effects; Beckmann, Jenkinson, & Smith, 2003; Woolrich, 2008; Woolrich, Behrens, Beckmann, Jenkinson, & Smith, 2004). At the group-level, analyses were completed using a mixed effects model that included both fixed effects and random effects from cross session/subject variance in FLAME. Again, Z (Gaussianised T/F) statistic images were then thresholded using clusters determined by Z>2.3 and a (Bonferroni corrected) cluster significance threshold of p=.05. Region of Interest Analysis A priori regions of interest (ROI) were the following regions of the human AON: inferior frontal gyrus pars opercularis (IFGo) and pars triangularis (IFGt), the parietal operculum (PO), the precentral gyrus (PCG), and supramarginal gyrus (anterior portion, SMGa and posterior portion, SGMp) for the left and right hemispheres (Caspers, Zilles, Laird, & Eickhoff, 2010; Cross, Kraemer, Hamilton, Kelley, & Grafton, 2009; Grafton, 2009; Small et al., 2012). All ROIs were defined through anatomically using the probabilistic thresholds of greater than 50% applied for each ROI (according to the Harvard-Oxford anatomical atlas). Mean percent signal change (% SC) within each ROI was extracted for each task condition and each participant using Featquery in FSL. Student’s un-paired t-test was calculated within a ROI to assess for significanct %SC difference between groups (ND, S) for contrasts of action execution and action observation. 90 Brain Behavior Analysis For each left and right hemisphere AON ROI (IFGo, IFGt, PCG, SMGa, SMGt), Spearman’s rho correlations were tested for individuals with stroke between ROI activity and motor scores for the Fugl-Meyer Assessment Lower Extremity (FMA-LE). Lesion Analysis Lesions were drawn semi-manually by a trained research assistant following a detailed lesion tracing protocol (Riley et al. 2011) using MRIcron (Rorden and Brett 2000). Semi- automated Robust Quantification of Lesions (SQRL) Toolbox was also developed and used for assessment of automated and manual lesion quantification (Ito, Anglin, & Liew, 2017). Lesion masks were then smoothed using a 2mm Gaussian kernel. For each subject, a small mask was manually created in the healthy white matter tissue of the contralesional hemisphere. The white matter mask was used to determine the mean and standard deviation of healthy white matter voxel intensities within each subject’s anatomical image using fslstats. Each subject’s anatomical image was then thresholded at one standard deviation away from the mean white matter intensity, such that voxels with a signal intensity within or above the normal range would be excluded from the final lesion mask. Finally, the volume of the lesion was calculated using fslstats. Lesion location for individuals with stroke is presented in Figure 2. Percent of Lesion Overlap with ROIs To examine the percent of lesion overlap with each ROI, each individual’s binary lesion 91 map was normalized to standard space. Each normalized lesion map was then masked with each ROI using fslmaths. The number of voxels in the overlapping area was obtained using the fslstats. The number of voxels in the overlapping area was then divided by the total number of voxels within the ROI to calculate the percent of overlap between the lesion and the ROI for each subject. RESULTS In the current study, we examined the representation of the AON for the lower extremity (LE), or foot, for non-disabled adults and individuals with stroke. We investigated the representation through main effect analyses and BOLD percent signal change in regions of interest (ROIs) of the AON. We also examined the relationship between behavioral assessments and brain activity. Whole brain fMRI Results Main effect of Action Observation During left lower extremity action observation (OBSL) compared to rest for the non- disabled group (ND), significant activity was found in the bilateral AON, including the bilateral inferior frontal gyrus, bilateral supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others (Table 3, Figure 3). During left (corresponding to non-paretic) lower extremity action observation (OBSL), for individuals with stroke group (S), significant, above threshold activity was found in the bilateral AON, including the bilateral inferior frontal 92 gyrus, bilateral supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among other regions (Table 3, Figure 3). During right lower extremity action observation (OBSR) for the non-disabled group (ND), significant activity was found in was found in the bilateral AON, including the bilateral inferior frontal gyrus, right supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others (Table 3, Figure 3). During right (corresponding to paretic) lower extremity action observation (OBSR) for individuals with stroke group (S), significant, above threshold activity was found in was found in the bilateral AON, including the bilateral inferior frontal gyrus, bilateral supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others (Table 3, Figure 3). Main Effect of Action Execution During left lower extremity action execution (EXEL) for the non-disabled group (ND), significant activity was found in bilateral AON, including the right inferior frontal gyrus, bilateral supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others (Table 4, Figure 3). During left (corresponding to non-paretic) lower extremity action execution (EXEL) for individuals with stroke group (S), significant, above threshold activity was found in right AON, right inferior frontal gyrus, right supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others (Table 4, Figure 4). During right lower extremity action execution (EXER) for the non-disabled group (ND), significant activity was found in bilateral AON, including the bilateral inferior frontal gyrus, bilateral supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, 93 among others (Table 4, Figure 3). During right (corresponding to paretic) lower extremity action execution (EXER) for individuals with stroke group (S), significant, above threshold activity was found in bilateral AON, including the right inferior frontal gyrus, bilateral supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others (Table 4, Figure 3). Main Effect of Action Imitation During left lower extremity action imitation (IMIL) for the non-disabled group (ND), significant activity was found in bilateral AON, including left inferior frontal gyrus, bilateral supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others (Table 5, Figure 3). During left (corresponding to non-paretic) lower extremity action imitation (IMIL) for individuals with stroke group (S), significant activity was found in parts of the AON, including left inferior frontal gyrus, bilateral precentral gyrus, and bilateral occipital cortices, among others (Table 5, Figure 3). During right lower extremity action imitation (IMIR) for the non-disabled group (ND), significant activity was found in bilateral AON, including bilateral inferior frontal gyrus, bilateral precentral gyrus, bilateral supramarginal gyrus, and bilateral occipital cortices, among others (Table 5, Figure 3). During right (corresponding to non-paretic) lower extremity action imitation (IMIR) for individuals with stroke group (S), significant activity was found in bilateral AON, including bilateral inferior frontal gyrus, bilateral precentral gyrus, and left supramarginal gyrus (Table 5, Figure 3). 94 Main Effect of Action Execution – Observation During left lower extremity action execution-observation (EXEL-OBSL) for the non- disabled group (ND), significant activity was found in right post central gyrus (Table 6, Figure 4). During left (corresponding to non-paretic) lower extremity action execution-observation (EXEL- OBSL) for individuals with stroke group (S), significant, above threshold activity was found in right post central gyrus (Table 6, Figure 4). During right lower extremity action execution-observation (EXER-OBSR) for the non- disabled group (ND), significant, above threshold activity was found in the bilateral AON, including the bilateral inferior frontal gyrus, bilateral supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others (Table 6, Figure 4). During right (corresponding to non-paretic) lower extremity action execution-observation (EXER-OBSR) for individuals with stroke group (S), significant, above threshold activity was found in the right AON, including the right inferior frontal gyrus, and right precentral gyrus, among others (Table 6, Figure 4). Main Effects Against Visual Control Observation-Control. During left lower extremity action observation- control (OBSL- control) for the non-disabled group (ND), significant activity was found in the bilateral AON, including right inferior frontal gyrus, and left supramarginal gyrus, and bilateral visual cortices. During left (corresponding to non-paretic) lower extremity action observation-control (OBSL- control) for individuals with stroke group (S), significant, above threshold activity was found in the bilateral AON, including right inferior frontal gyrus, bilateral supramarginal gyrus, and 95 bilateral precentral gyrus, and bilateral occipital cortices, among others. During right lower extremity action observation-control (OBSR-control) for the non-disabled group (ND), significant activity was found in bilateral occipital cortices. During right (corresponding to non-paretic) lower extremity action observation-control (OBSR-control) for individuals with stroke group (S), significant activity was found in the AON, including bilateral supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others. Execution-Control. During left lower extremity action execution- control (EXEL-control) for the non-disabled group (ND), significant activity was found in visual and motor areas, but not in the AON. During left (corresponding to non-paretic) lower extremity action execution- control (EXEL-control) for individuals with stroke group (S), significant activity was found in the right AON, including the right inferior frontal gyrus, right supramarginal gyrus, and right precentral gyrus, and bilateral occipital cortices, among others. During right lower extremity action execution-control (EXER-control) for the non-disabled group (ND), significant activity was found in the bilateral AON, including right inferior frontal gyrus, bilateral supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others. During right (corresponding to non-paretic) lower extremity action execution-control (EXER-control) for individuals with stroke group (S), significant activity was found in the bilateral AON, including the right inferior frontal gyrus, bilateral supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others. Imitation-Control. During left lower extremity action imitation- control (IMIL-control) for the non-disabled group (ND), significant, above threshold activity was found in bilateral visual cortices. During left (corresponding to non-paretic) lower extremity action imitation-control 96 (IMIL-control) for individuals with stroke group (S), significant activity was found in right AON, including right inferior frontal gyrus, right supramarginal gyrus, and right precentral gyrus, and bilateral occipital cortices, among others. During right lower extremity action imitation-control (IMIR-control) for the non-disabled group (ND), significant activity was found in the bilateral occipital cortices. During right (corresponding to non-paretic) lower extremity action imitation- control (IMIR-control) for individuals with stroke group (S), significant activity was found in bilateral AON, including right inferior frontal gyrus, right supramarginal gyrus, and bilateral precentral gyrus, and bilateral occipital cortices, among others. Region of Interest Percent BOLD Signal Change Results Percent BOLD signal change (%SC) for the AON ROIs of inferior frontal gyrus pars opercularis, inferior frontal gyrus, pars triangularis, precentral gyrus, supramarginal gyrus anterior portion, and supramarginal gyrus posterior portion for the left and right hemispheres were calculated through FSL featquery. Within group comparisons were conducted using Student’s t-test and between group comparisons were conducted using Welch’s t-test (Table 7). Using paired t-test in the non-disabled group, we find statistically significant differences in %SC comparing observation-rest to execution-rest in the following ROIs: IFGo_L (p=.047) for the right LE, IFGt_L for left LE (p=.024), PCG_L for right LE (p=.001), PCG_R for right LE (p=.026), SMGp_L for right LE (p=.033). All other ROIs contained no significant differences between conditions in the non-disabled group. Using paired t-test in the stroke group, we find statistically significant differences in %SC comparing observation-rest to execution-rest in the following ROIs: IFGt_L for both left (p=.024) 97 and right (p=.014) LE, and PCG_L for right LE (p=.033). All other ROIs contained no significant differences between conditions in the stroke group. Using Welch’s t-test to compare between stroke and non-disabled groups, we find no statistically significant differences in %SC within ROIs. One ROI, PCG_L approaches significance for OBSR-rest (p=.0803). Brain Behavior Results FMA-LE scores in the stroke group significantly correlate with ROI activity in IFGo_L during right action execution (EXER-rest, r= .506, p=.045) and right action execution minus observation (EXER-OBSR, r=.542, p=.030). Other regions were found to be approach significance (Table 8). DISCUSSION In this study, we examined the cortical motor representation of the Action Observation Network (AON) for the lower extremity (LE). Our results support our hypothesis that a there is a distributed representation for the AON for the lower extremity in individuals with stroke and non-disabled adults. In line with our hypothesis, for the main effect analyses, we see bilateral BOLD activity in the AON (IFG, SMG, PCG) for non-disabled adults for left and right action observation, execution, and a subtraction contrast of execution – observation in a whole brain fMRI analysis. For individuals with stroke, we also see bilateral AON activity (IFG, SMG, PCG) during action observation. This is the first time AON activity for the lower extremity has been examined to 98 this detail not only in a non-disabled group, but also in a stroke group. The results indicate that individuals with stroke largely show similar patterns for action observation, execution, and imitation, to the non-disabled group. For action execution, we find activity that appears to be greater in the right-hemisphere. Specifically, activity is stronger in the right IFG and right SMG during action execution of both left and right actions; and for the right IFG and right PCG during a subtraction contrast of execution – observation for right actions only. While this result needs to be corroborated with laterality index analyses, it may suggest that during action execution, activity of the AON after stroke appears to be stronger in the contralesional (right) hemisphere. Evidence suggests that greater activity in the ipsilesional hemisphere after stroke promotes recovery of motor function (Grefkes et al., 2008; Marshall et al., 2000; Nudo, 2006; Richards, Stewart, Woodbury, Senesac, & Cauraugh, 2008; Ward & Cohen, 2004). However, in our study, there appears to be greater contralesional activity during execution and bilateral AON activity during observation. This contralesional activity may facilitate control of recovered motor function by operating at a higher-order processing level, similar to but not identical with the extended network concerned with complex movements in non-disabled subjects (Gerloff et al., 2006). Other studies suggest increased contralesional motor network activity after stroke may be an adaptive mechanism (Braun et al., 2007; Calautti et al., 2003) perhaps due to less physiological hemisphere activation balance (Calautti et al., 2003) or that individuals with greater damage to the corticospinal tract engage contralesional brain networks to a higher degree (Calautti et al., 2007). 99 In a ROI analysis of percent BOLD signal change with observation and execution, for non-disabled group, we found significant activity in multiple regions of the AON, including bilateral IFGo, left IFGt, bilateral PCG, and left SMG. For the stroke group, we found significant activity for the left IFGt and left PCG only. Such results may suggest that, in looking at percent signal change for ROIs, individuals with stroke engage ipsilesional AON. Previous research corroborates this finding for the upper extremity and suggests that such ipsilesional activity promotes neural recovery (Marshall et al., 2000; Nudo, 2006; Ward & Cohen, 2004). In looking at behavioral measures for the stroke group, brain activity during right hand action execution and execution-observation showed significant correlation with ROI activity in left IFGo, suggesting the greater the FMA-LE score (less impaired), the greater the activity in the left IFGo. LIMITATIONS & FUTURE DIRECTIONS We acknowledge the limitations of this study, beginning with our small group sample size. While previous research has found modest AON activity effects for group samples of n=12 individuals with stroke (Garrison et al., 2013), power analysis suggests a larger sample size is necessary for an appropriate effect size. Replication of this work in a larger sample would improve our understanding of how the current findings relate to individuals after stroke. Participant movement is also a strong factor in this study and much of our current data analysis surrounded removal of motion in the scanner. It is possible that such a removal of voxels and components may provide different results with versus without the removal. Future studies of execution and/or imitation of tasks should consider difficulty of the task and 100 feasibility for individuals with stroke to correctly perform the task in the scanner with minimal movement. Further variables of lesion location and variability in lesion type, size, and vasculature affected also cause additional variance in the data. While such heterogeneity is common in the stroke population at large, studies with multiple variables are difficult to interpret, at best. Our attempts to disentangle the results of this study are prominent, yet, homogeneous group populations make for stronger claims. Future work of the AON representation of the LE for skilled or learned movement is still necessary. Examples of questions still to be asked include (1) investigating if activity shifts from the contralesional to ipsilesional hemisphere to a more bilateral distribution during action observation of the upper versus lower extremity, or (2) determining if there exists such a right hemisphere dominant activity for action execution of upper extremity, similar to the lower extremity activity described in this study. Additional types of analyses, specifically questions regarding analyses differences between main effect versus ROI percent signal change should also be considered. Debate exists over use of %SC and scaling factors of the output data and interpretations of fMRI results (Mumford, n.d.; Pernet, 2014; Yarkoni, 2009). A formal laterality index study of the current work would be needed to quantify hemispheric activity. Additional analyses using masked ROIs or functional localizers could help elucidate differences between types of analyses. Future studies should increase the number of individuals for each stroke group and, with this increased statistical power, determine correlations between lesion location and activity of the AON. 101 In addition to research on the task-based activity of the AON, future studies may also ask questions about resting state fMRI and AON activity after stroke. Such multifaceted research on the AON will allow us to understand changes in the neural circuitry post stroke. With this understanding, we can begin to determine what types of conditions engage the AON and, potentially, determine what types of tasks are clinically useful for AOT. CONCLUSION This study supports our hypothesis that there exists a distributed representation where the AON is engaged for lower extremity action observation, imitation, and execution in individuals with stroke. The clinical implications of such a finding remain to be explored, yet the basic science suggests a similar lower extremity representation for non-disabled and individuals with stroke. This may support the notion that AOT might be effective for lower extremity disabilities, yet additional research is required before such a claim can be made. Understanding of the neural circuitry and functional activity of the AON, and individual differences in activity of the AON may allow us to develop personalized rehabilitation protocols for patients after stroke. Development of clinical and interventional studies incorporating the AON and LE for post-stroke rehabilitation would be a necessary future step on this path. 102 Figure 3.1. Stimuli for fMRI study of the AON for Lower Extremity. The fMRI paradigm was a block design in which participants (1) observe videos of left or right foot actions (OBSL, OBSR), (2) execute from a cue on still images of a left or right foot (EXEL, EXER), (3) imitate from a cue on a video of a left or right foot (IMIL, IMIR), (4) observed a green ball (control), or (5) observed a fixation cross (rest). Actions required plantar flexion of the foot towards a rectangle to the left or right, to the best of the participant’s capability. 103 Figure 3.2. Lesion Masks of Individuals with Lower Extremity Stroke. Semi-manual drawn masks of lesions of 3 individuals with stroke are presented. Lesions are depicted in yellow in the coronal and axial views of three study participants. As is depicted through the different sizes and locations of the yellow lesion mask, there is variety in the study participants’ lesion size and location, resulting in differences in behavioral measures. 104 Figure 3.3. Whole brain activity during left and right hand observation, execution, and imitation for non-disabled and individuals with stroke affecting the lower extremity. Top: Observation – rest, Middle: Execution – rest, Bottom: Imitation – rest. Nondisabled individuals are represented in blue. Individuals with stroke are represented in red. Overlap between groups is represented in purple. Z=2.3, corrected for multiple comparisons. 105 Figure 3.4. Whole brain activity overlap for left and right action execution-observation of the lower extremity (LE) for non-disabled and individuals with stroke. Top: Action Execution – Observation for Left LE (EXEL-OBSL), Bottom: Action Execution – Observation for Right LE (EXER- OBSR). Nondisabled individuals are represented in blue. Individuals with stroke are represented in red. Overlap between groups is represented in purple. Z=2.3, corrected for multiple comparisons. 106 107 Figure 3.5 (Supplementary) Score sheet for Fugl-Meyer Assessment Lower Extremity. Individuals with stroke were assessed for lower extremity motor function, balance, sensation, and joint function in hemiplegic patients. This exam was conducted and scored by a certified, trained, and blinded Occupational Therapist (OT) with no other involvement of the study. For the purpose of this study, the FMA-LE was modified to include motor function sections E & F (Lower Extremity & Coordination/Speed) for a total score of 34. 108 Table 3.1. Demographics of Stroke (S) and Non-Disabled (ND) groups. The study involved 28 total individuals (n=16 Stroke, n=12 ND). Demographics of participants are presented. 109 Table 3.2. Demographics and Lesion Information of Stroke (S) group. Participants with stroke demographics and lesion information are presented. Sub-groups included type of stroke (ischemic or hemorrhagic), Vasculature (Middle Cerebral Artery, Anterior Cerebral Artery, Basilar Artery), Lesioned Vascular Territory (Internal Capsule, Internal Capsule + Cortex, Non- Internal Capsule). Behavioral assessment score of the Fugl-Meyer Assessment for the Lower Extremity was is also presented. L = Left, MCA = Middle Cerebral Artery, ACA = Anterior Cerebral Artery, IC = Internal Capsule, IC+ = Internal Capsule + Cortex, Non-IC = Non-Internal Capsule, FMA-LE = Fugl Meyer- Assessment Lower Extremity 110 Table 3.3. Main effect of action observation of left and right foot actions. Peak activations during left and right foot action observation (plantar flexion eversion and inversion) for non- disabled participants and participants with stroke. 111 Table 3.4. Main effect of action execution of left and right foot actions. Peak activations during left and right foot action execution (plantar flexion eversion and inversion) for non- disabled participants and participants with stroke. 112 Table 3.5. Main effect of action imitation of left and right foot actions. Peak activations during left and right foot action imitation (plantar flexion eversion and inversion) for non-disabled participants and participants with stroke. 113 Table 3.6. Brain activity compared between action execution and action observation of left and right foot actions. Peak activations for execution-observation for left and right foot actions (plantar flexion eversion and inversion) for non-disabled participants and participants with stroke. 114 Table 3.7. Percent BOLD Signal Change within ROI. Percent BOLD Signal Change (%SC) for the AON ROIs of inferior frontal gyrus pars opercularis (IFGo), inferior frontal gyrus, pars triangularis (IFGt), precentral gyrus (PCG), supramarginal gyrus anterior portion (SMGa), and supramarginal gyrus posterior (SMGp) portion for the left and right hemispheres. Signal change is extracted from contrasts for left and right lower extremities of observation-rest (OBSR, OBSL) and execution-rest (EXER, EXEL). 115 Table 3.8. Brain Behavior correlation of Percent BOLD Signal Change within ROI. Motor scores of the Fugl-Meyer Assessment for Lower Extremity (FMA-LE) are correlated to percent BOLD signal change (%SC) for the AON ROIs of inferior frontal gyrus pars opercularis (IFGo), inferior frontal gyrus, pars triangularis (IFGt), precentral gyrus (PCG), supramarginal gyrus anterior portion (SMGa), and supramarginal gyrus posterior (SMGp) for left and right hemispheres. 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Here, I aim to summarize the results of the studies and provide concluding remarks regarding differences in the AON for upper versus lower extremities. Additionally, I will discuss future directions for further studying the AON in individuals with stroke. ENGAGEMENT OF THE AON FOR THE UE In chapter 2, I examined brain activity of the AON between contrasts of action imitation, execution, and observation in non-disabled adults and individuals with stroke affecting the upper extremity (UE). As predicted, I found activity in the AON for each contrast for the non-disabled and stroke groups. In order to test our hypothesis of imitation>execution>observation, I analyzed two subtraction contrasts: execution-observation and imitation-execution. Results suggested specifically, in execution – observation of the (a) left hand, bilateral AON activity for both groups; and in the (b) right hand, bilateral AON activity for the ND and only right AON for the S group. Imitation – execution of the (a) left hand showed AON activity for both groups; and (b) right hand showed bilateral SMG activity for ND and right SMG activity in the S group. These findings suggest that there is bilateral AON recruitment in ND individuals, but only unilateral right recruitment in individuals with stroke for the right (disabled) hand. These results are 127 concordant with suggesting greater activity in the ipsilesional hemisphere after stroke promotes recovery of motor function (Grefkes et al., 2008; Marshall et al., 2000; Nudo, 2006; Richards, Stewart, Woodbury, Senesac, & Cauraugh, 2008; Ward & Cohen, 2004). In looking at behavioral measures for the stroke group, brain activity during right hand action execution and execution-observation showed significant correlation with ROI activity in left IFGo, suggesting the greater the FMA-LE score (less impaired), the greater the activity in the left IFGo. I had hypothesized that activity of imitation would be greater than activity of execution, and execution would be greater than observation (imitation>execution>observation). I found this relationship to exist for ND group in the bilateral PCG for left and hand and right SMGa for the right hand. This pattern existed in more AON regions for the S group: for the left hand, in the left IFGo, right IFGt, bilateral SMG and for the right (paretic) hand in the bilateral IFGo, and right PCG. Such analyses suggest that imitation engages the AON the most in the IFGo for the stroke group for the paretic hand. It has been described that imitation recruits additional brain regions over those recruited by execution or observation alone (Rossini et al., 2007) and that there is a significant difference with greater signal intensity for imitation than execution or observation alone (Iacoboni et al., 1999). We find that in the IFGo, a key ROI in the AON, the activity follows imitation>execution>observation, suggesting that imitative learning may greatly recruit the IFGo. However, other ROIs (PCG, SMG), there is greater engagement in the reverse contrast (i.e. imitation<execution>observation), suggesting that in these regions, execution engages these ROIs more than imitation. We speculate that, perhaps, engagement of AON may be ROI-specific and that different ROIs function as separate nodes within this network, not that all nodes are engaged similarly. Additional analyses are required to assess this claim. 128 ENGAGEMENT OF THE AON FOR LE In chapter 3, I examined, for the first time, the cortical motor representation of the Action Observation Network (AON) for the lower extremity (LE). The results support the hypothesis that there is a distributed representation for the AON for the lower extremity in ND and S. Support for the hypothesis comes from the fact that the main effect analyses shows bilateral BOLD activity in the AON (IFG, SMG, PCG) in ND for left and right action observation, execution, and the contrast between execution and observation in a whole brain fMRI analysis. For the S group, I also show bilateral AON activity (IFG, SMG, PCG) during action observation. I am excited to share this data, as it is the first time AON activity for the lower extremity has been examined to this detail not only in a non-disabled individuals, but also in stroke individuals. The results indicate that individuals with stroke largely show patterns for action observation, execution, and imitation similar to those seen non-disabled individuals. For action execution, activity appears to be greater in the right-hemisphere. Specifically, activity is stronger in the right IFG and right SMG during action execution of both left and right extremities; right IFG and right PCG show stronger activity in the contrast between execution and observation only for right actions. While this result needs to be corroborated with laterality index analyses, it may suggest that during action execution, activity of the AON after stroke appears to be stronger in the contralesional (right) hemisphere when dealing with a lower extremity deficits. In the upper extremity, prior results suggest that greater activity in the ipsilesional hemisphere after stroke promotes recovery of motor function (Grefkes et al., 2008; Marshall et al., 2000; Nudo, 2006; Richards et al., 2008; Ward & Cohen, 2004). However, in our study, we 129 find greater contralesional activity during execution and bilateral AON activity during observation for the lower extremity. Differences in AON engagement per extremity will be addressed in the next section. Theoretically, this contralesional activity may facilitate control of recovered motor function by operating at a higher-order processing level, similar to, but not identical with, the network associated with planning and executing complex movements in non- disabled subjects (Gerloff et al., 2006). Other studies suggest increased contralesional motor network activity after stroke may be an adaptive mechanism (Braun et al., 2007; Calautti et al., 2003) perhaps due to less physiological hemisphere activation balance (Calautti et al., 2003) or that individuals with greater damage to the corticospinal tract engage contralesional brain networks to a higher degree (Calautti et al., 2007). In a ROI analysis of percent BOLD signal change with observation and execution, for non-disabled group, significant activity is shown in multiple regions of the AON, including bilateral IFGo, left IFGt, bilateral PCG, and left SMG. For the stroke group, we found significant activity for the left IFGt and left PCG only. Such results may suggest that, in looking at percent signal change for ROIs, individuals with stroke engage ipsilesional AON. While research for the lower extremity on this topic has not been conducted, previous research corroborates this finding for the upper extremity and suggests that such ipsilesional activity promotes neural recovery (Marshall et al., 2000; Nudo, 2006; Ward & Cohen, 2004). DIFFERENCES BETWEEN THE UE AND LE In this dissertation, I have presented engagement of the AON separately for each extremity (upper and lower); however, few cases of stroke are extremity-specific. Often, the 130 same stroke patients will have impairments in both the hands and feet. In an attempt to understand differences between the hands and feet for the same network, we compared activity for the same contrasts for the hands and feet. It should be noted this is a preliminary analysis—limitations include differences in subject size between the two groups, different MRI scanners, and different stimuli—however, interesting results were shown. During all three conditions (observation, execution, imitation) there is more activity in the AON for the hands than feet (Figures 1-3). However, there is more activity for the hands in the PCG and for the feet in the IFG. Such results show that differences within the AON, where different ROIs are engaged for different conditions, suggesting that perhaps nodes within the AON are recruited differently. Further differences in engagement of the AON for left and right extremity varied by condition, yet appears to follow the non-dominant extremity (left in ND and right in S). The preliminary results suggest differences between the extremity (upper versus lower) for condition (imitation, execution, observation); however, additional studies must be conducted before these differences can be further elucidated. FUTURE DIRECTIONS Future directions and additional research regarding activity of the AON for individual with stroke is required to allow us to better understand this network. Studies with larger sample sizes may provide additional power to the claims advanced in this dissertation. Laterality index analyses may shed light on hemispheric differences in AON activity for individuals with stroke affecting the lower extremity, as well as engagement of the AON for 131 different conditions of imitation, execution, and observation. Potential work on subject specific AON ROIs may allow percent signal change results to be more applicable to a population of individuals with stroke. This dissertation uses standardized structural ROIs; however, we know that representations of ROIs for stroke subjects shifts, suggesting that subject specificity is important to consider. Furthermore, in investigating extremity-specific engagement of the AON, additional studies should be conducted that use the same subjects within one scan, with stimuli specific to the upper and lower extremity. Lastly, application of the presented protocol and analyses of diffusion fractional anisotropy (through diffusion tensor imaging) and AON activity may provide information about the relationship between structure and function. A potential protocol for this type of analysis is presented in Appendix B. Overall, this dissertation has provided information to begin to address the gap in knowledge regarding the engagement of the AON. A further understanding of this network, effector specificity, conditions that engage it, and the relationship between structure of white matter tracts and functional activity of this network are necessary before therapeutic approaches based on this network, such as AOT, can be suggested to patients as a rehabilitation approach. This dissertation points to the need to continued work to address the topic and provide information to better inform the development of therapies for post-stroke rehabilitation. 132 REFERENCES Braun, C., Staudt, M., Schmitt, C., Preissl, H., Birbaumer, N., & Gerloff, C. (2007). Crossed cortico-spinal motor control after capsular stroke. The European Journal of Neuroscience, 25(9), 2935–45. https://doi.org/10.1111/j.1460-9568.2007.05526.x Calautti, C., Baron, J.-C., Cameirao, M. S., Baron, J.-C., Badia, S. B. i, Oller, E. D., & Verschure, P. F. M. J. (2003). Functional neuroimaging studies of motor recovery after stroke in adults: a review. 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P., Brass, M., Bekkering, H., Mazziotta, J. C., Rizzolatti, G., & Lacoboni, M. (1999). Cortical Mechanisms of Human Imitation. Source: Science, New Series, 286(5449), 2526–2528. Retrieved from http://www.jstor.org/stable/2899889 Marshall, R. S., Perera, G. M., Lazar, R. M., Krakauer, J. W., Constantine, R. C., & DeLaPaz, R. L. 133 (2000). Evolution of Cortical Activation During Recovery From Corticospinal Tract Infarction. Stroke, 31(3). Retrieved from http://stroke.ahajournals.org.libproxy1.usc.edu/content/31/3/656.long Nudo, R. J. (2006). Mechanisms for recovery of motor function following cortical damage. Current Opinion in Neurobiology, 16(6), 638–644. https://doi.org/10.1016/j.conb.2006.10.004 Richards, L. G., Stewart, K. C., Woodbury, M. L., Senesac, C., & Cauraugh, J. H. (2008). Movement-dependent stroke recovery: A systematic review and meta-analysis of TMS and fMRI evidence. Neuropsychologia, 46(1), 3–11. https://doi.org/10.1016/j.neuropsychologia.2007.08.013 Rossini, P. M., Altamura, C., Ferreri, F., Melgari, J.-M., Tecchio, F., Tombini, M., … Vernieri, F. (2007). Neuroimaging experimental studies on brain plasticity in recovery from stroke. Europa Medicophysica, 43(2), 241–254. Retrieved from http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=17589415 &retmode=ref&cmd=prlinks Ward, N. S., & Cohen, L. G. (2004). Mechanisms underlying recovery of motor function after stroke. Archives of Neurology, 61(12), 1844–8. https://doi.org/10.1001/archneur.61.12.1844 134 Figure 4.1. AON extremity-specific engagement during action observation. Top panel shows activity of the AON for the upper extremity (hand) and bottom panel shows activity of the AON for the lower extremity (foot) during action observation. Brain activity is separated by hemisphere and left versus right extremity. 135 Figure 4.2. AON extremity-specific engagement during action execution. Top panel shows activity of the AON for the upper extremity (hand) and bottom panel shows activity of the AON for the lower extremity (foot) during action execution. Brain activity is separated by hemisphere and left versus right extremity. 136 Figure 4.3. AON extremity-specific engagement during action imitation. Top panel shows activity of the AON for the upper extremity (hand) and bottom panel shows activity of the AON for the lower extremity (foot) during action imitation. Brain activity is separated by hemisphere and left versus right extremity. 137 APPENDIX A: BEHAVIORAL ASSESSMENTS Fugl-Meyer Assessment Scale Description This assessment is a measure of upper extremity (UE) and lower extremity (LE) motor and sensory impairment. Equipment A chair, bedside table, reflex hammer, cotton ball, pencil, small piece of cardboard or paper, small can, tennis ball, stop watch, and blindfold. Administration Perform the assessment in a quiet area when the patient is maximally alert. The complete assessment usually requires 45 minutes. GENERAL RULES Perform the assessment in a quiet area when the patient is maximally alert. Volitional movement assessment: This includes flexor synergy, extensor synergy, movement combining synergies, movement out of synergy, wrist, hand, and coordination/speed. For all tests of volitional motion, these guidelines are to be followed: 1.Give clear and concise instructions. Mime as well as verbal instructions permissible. 2.Have subject perform the movement with non-affected extremity first. 3.Repeat each movement 3x on the affected side and score best performance. If full score is attained on trials 1 or 2, do not have to repeat 3 times. Only test Coordination/speed, one time. 4.Do not assist subject, however verbal encouragement is permitted. 5.Test the wrist and hand function independently of the arm. During the wrist tests (items 7a- e), support under the elbow may be provided to decrease demand at the shoulder; however, the subject should be activating the elbow flexors during the elbow at 90 degree tests and activating the elbow extensors during the elbow at 0 degree tests. In contrast, assistance can be provided to the arm at the elbow and just proximal to the wrist in order to position the arm during the hand tests (items 8a-g). Lower Extremity I. Reflex activity (1a and 1b) •Subject is supine or sitting. •Attempt to elicit the Achilles and patellar reflexes. •Assess the unaffected side first. •Test affected side. •Scoring (Maximum possible score = 4): - (0) - No reflex activity can be elicited; - (2) - Reflex activity can be elicited. Items to be scored are Achilles and patellar reflexes. 138 IIA. Flexor synergy (2a, 2b, 2c) •Subject is supine. •Have participant perform movement with unaffected side first. •On the affected side, check subject’s available PROM at each joint to be tested. •Start with leg fully extended at hip, knee, and ankle. Instruct the subject to “bring your knee to your chest” (therapist is observing for evidence of hip, knee, ankle flexion in order to assess the presence of all components of the flexor synergy). Therapist can cue the participant to move any missing component. •Test 3x on the affected side and score best movement at each joint. •Scoring (Maximum possible score = 6): - (0) - Cannot be performed at all - (1) – Partial motion - (2) – Full motion Items to be scored are: Hip flexion, knee flexion, ankle dorsiflexion. IIB. Extensor synergy (2d, 2e, 2f, 2g) •Subject is sidelying. •Have participant perform movement with unaffected side first. •On the affected side, check subject’s available PROM at each joint to be tested. •Start in 90 degrees hip flexion, 90 degrees knee flexion and ankle dorsiflexion. •Instruct the subject to "push your foot down and kick down and back”. (Ankle plantarflexion, knee extension, hip adduction and hip extension.) •Slight resistance should be applied in adduction which is gravity-assisted in this position to ensure subject is actively doing it. •Test 3x on the affected side and score best movement at each joint. •Scoring (Maximum possible score = 8): - (0) – No motion - (1) – Partial motion - (2) – Full motion Items to be scored are: Hip extension, hip adduction, knee extension, ankle plantarflexion. III. Movement combining synergies (in sitting) (3a, 3b) 3a. Knee flexion beyond 90°: •Subject is sitting, feet on floor, with knees free of chair. Knee to be tested is slightly extended beyond 90° knee flexion. Calf muscles should not be on stretch. To decrease friction, subject’s shoes can be removed, but socks should remain on. •Have participant perform movement with unaffected side first. •Subject is instructed to "pull your heel back and under the chair." •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – No active motion - (1) – From slightly extended position, knee can be flexed but not beyond 90° - (2) – Knee flexion beyond 90° 3b. Ankle Dorsiflexion 139 •Subject is sitting, feet on floor, with knees free of chair. Calf muscles should not be on stretch. •Have participant perform movement with unaffected side first. •On the affected side, check subject’s available PROM at the ankle joint. •Subject is instructed to "keeping your heel on the floor, lift your foot." •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2) - (0) – No active motion - (1) – Incomplete active flexion (heel must remain on floor with medial and lateral borders of the forefoot clearing the floor during dorsiflexion) - (2) – Normal dorsiflexion (full within available ROM, heel remains on the floor) IV. Movement out of synergy (Standing, hip at 0 degrees) (4a, 4b) 4a. Knee Flexion: •Subject is standing, hip at 0 degrees (or full available ROM up to 0 degrees). On leg that is being tested, hip is at 0 degrees (or full available ROM up to 0 degrees), but the knee is flexed, and the subject’s toes are touching the floor slightly behind. Evaluator can provide assistance to maintain balance and subject can rest hands on a table. •Have participant perform movement with unaffected side first. •Subject is instructed to "keeping your hip back, kick your bottom with your heel." •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – Knee cannot flex without hip flexion - (1) – Knee flexion begins without hip flexion but does not reach to 90° or hip begins to flex in later phase of motion - (2) – Knee flexion beyond 90° (Knee flexion beyond 90 degrees with hip maintained in extension) 4b. Ankle Dorsiflexion: •Subject is standing, hip at 0 degrees. If subject’s calf muscle length is limiting active dorsiflexion in this starting position, then leg that is being tested can be positioned forward, so the hip is at approximately 5 degrees of flexion, and calf muscles are in lengthened position. Knee must stay fully extended. Evaluator can provide assistance to maintain balance and subject can rest hands on a table. •Have participant perform movement with unaffected side first. •On the affected side, check subject’s available dorsiflexion PROM. •Subject is instructed to "keeping your knee extended and your heel on the floor, lift your foot." •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – No active motion - (1) – Partial motion (less than full available range with knee extended; heel must remain on floor with medial and lateral borders of the forefoot clearing the floor during dorsiflexion) - (2) – Full motion (within available dorsiflexion range with knee extended and heel on the floor) 140 V.Normal Reflexes (sitting) (5) •ONLY DONE IF THE SUBJECT ATTAINS A SCORE OF 4 ON SECTION IV •(i.e., if the subject does not score a 2 on each of the previous items, then score this item 0). •The examiner shall elicit patellar and Achilles phasic reflexes with a reflex hammer and knee flexors with quick stretch of the affected leg and note if the reflexes are hyperactive or not. •Scoring (Maximum possible score = 2): - (0) - At least 2 of the 3 phasic reflexes are markedly hyperactive - (1) – One reflex is markedly hyperactive or at least 2 reflexes are lively - (2) - No more than one reflex is lively and none are hyperactive VI. Coordination/speed - Sitting: Heel to opposite knee repetitions in rapid succession. (6a, 6b, 6c) •Subject positioned in sitting with eyes open. •Have participant perform movement with unaffected side first. •Subject is instructed to "Bring your heel from your opposite ankle to your opposite knee, keeping your heel on your shin bone, move as fast as possible." •Use a stopwatch to time how long it takes the subject to do 5 full (ankle to knee to ankle) repetitions. •Use the full achieved active ROM in the unaffected limb as the comparison for the affected limb. If active ROM of affected limb is significantly less than that of affected limb, participant should be scored “0” for speed. •Repeat the same movement with the affected leg. Record the time for both the unaffected and affected sides. Observe for evidence of tremor or dysmetria during the movement •Scoring Tremor (Maximum possible score = 2): - (0) - Marked tremor - (1) – Slight tremor - (2) – No tremor •Scoring Dysmetria (Maximum possible score = 2): - (0) - Pronounced or unsystematic dysmetria - (1) – Slight or systematic dysmetria - (2) – No dysmetria •Scoring Speed (Maximum possible score = 2): - (0) - Activity is more than 6 seconds longer than unaffected leg - (1) – 2-5.9 seconds longer than unaffected leg - (2) - less than 2 seconds difference •NOTE: This item attempts to discriminate between basal ganglia, thalamic, or cerebellar strokes in which tremor or dysmetria may result as a direct result of lesion to these areas. The majority of stroke cases are in the middle cerebral artery or basilar artery where we expect to observe paralysis that affects movement speed but does not cause tremor or dysmetria. In cases of complete paralysis, observe for any indication of tremor or dysmetria that may be evident in face, voice, arms or legs. If there are no indicators of tremor or dysmetria, then score these items 2 and score speed 0. 141 Upper Extremity I. Reflex activity (1a, 1b) •Subject is sitting. •Attempt to elicit the biceps and triceps reflexes. •Test reflexes on unaffected side first. •Test affected side. •Scoring (Maximum possible score = 4): - (0) - No reflex activity can be elicited - (2) - Reflex activity can be elicited II.Flexor synergy (2a, 2b, 2c, 2d, 2e, 2f) •Subject is sitting. •Have participant perform movement with unaffected side first. •On the affected side, check subject’s available PROM at each joint to be tested. •Instruct the patient to fully supinate his/her forearm, flex the elbow, and bring the hand to the ear of the affected side. The shoulder should be abducted at least 90 degrees. •The starting position should be that of full extensor synergy. If the patient cannot actively achieve the starting position, the limb may be passively placed extended towards opposite knee in shoulder adduction/internal rotation, elbow extension, and forearm pronation. •Test 3x on the affected side and score best movement at each joint. •Scoring (Maximum possible score = 12): - (0) - Cannot be performed at all - (1) - Performed partly - (2) - Performed faultlessly Items to be scored are: Elevation (scapular), shoulder retraction (scapular), shoulder abduction (at least 90 degrees) and external rotation, elbow flexion, and forearm supination. III.Extensor synergy (3a, 3b, 3c) •Subject is sitting. •Have participant perform movement with unaffected side first. •On the affected side, check subject’s available PROM at each joint to be tested. •Instruct the patient to adduct & internally rotate the shoulder, extend his arm towards the unaffected knee with the forearm pronated. •The starting position should be that the limb is passively placed at patient’s side in elbow flexion and supination. The examiner must ensure that the patient does not rotate and flex the trunk forward, thereby allowing gravity to assist with the movement. The pectoralis major and triceps brachii tendons may be palpated to assess active movement. 142 •Test 3x on the affected side and score best movement at each joint. •Scoring (Maximum possible score = 6): - (0) - Cannot be performed at all - (1) - Performed partly Items to be scored are: Shoulder adduction/internal rotation, elbow extension, and forearm pronation. IV. Movement combining synergies (4a, 4b, 4c) The patient is asked to perform three separate movements: 4a. Hand to lumbar spine: •Subject is sitting with hand resting on lap. •Have participant perform movement with unaffected side first. •Subject is instructed to actively position the affected hand on the lumbar spine by asking them to “put your hand behind your back”. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – No specific action is performed (or patient moves but does not reach ASIS) - (1) - Hand must pass anterior superior iliac spine (performed partly) - (2) - Performed faultlessly (patient clears ASIS and can extend arm behind back towards sacrum; full elbow extension is not required to score a 2) 4b. Shoulder flexion to 90°, elbow at 0°: •Subject is sitting with hand resting on lap. •Have participant perform movement with unaffected side first. •On the affected side, check subject’s available PROM for shoulder flexion to 90° and full elbow extension. •Subject is instructed to flex the shoulder to 90°, keeping the elbow extended. The elbow must be fully extended throughout the shoulder flexor movement; the forearm can be in pronation or in a mid-position between pronation and supination. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – Arm is immediately abducted, or elbow flexes at start of motion - (1) - Abduction or elbow flexion occurs in later phase of motion - (2) - Performed faultlessly (patient can flex shoulder keeping elbow extended) 4c. Pronation/supination of forearm, elbow at 90°, shoulder at 0°: •Subject is sitting with arm at side, elbow flexed, and forearm in supination. •Have participant perform movement with unaffected side first. •On the affected side, check subject’s available PROM for end range of pronation and supination. •Subject is instructed to actively flex the elbow to 90° and pronate/supinate the forearm through the full available ROM. 143 •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) - Correct position of shoulder held in adduction at side of body and elbow flexion cannot be attained, and/or pronation or supination cannot be performed at all - (1) - Active pronation or supination can be performed even within a limited range of motion, and at the same time the shoulder and elbow are correctly positioned. V. Movement out of synergy (5a, 5b, 5c) The patient is asked to perform three separate movements: 5a. Shoulder abduction to 90°, elbow at 0°, and forearm pronated: •Subject is sitting with arm and hand resting at side. •Have participant perform movement with unaffected side first. •Subject is instructed to abduct the shoulder to 90°, in a pure abduction motion, with the elbow fully extended and the forearm pronated. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – Initial elbow flexion occurs, or any deviation from pronated forearm occurs - (1) - Motion can be performed partly, or, if during motion, elbow is flexed, or forearm cannot be kept in pronation; - (2) - Performed faultlessly (patient can fully abduct shoulder, keeping forearm pronated with no elbow flexion) 5b. Shoulder flexion from 90°-180°, elbow at 0°, and forearm in mid-position: •Subject is sitting with elbow extended, hand resting on knee. •Have participant perform movement with unaffected side first. •Subject is instructed to flex the shoulder above 90°, with the elbow fully extended and the forearm in the midposition between pronation and supination. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – Initial flexion of elbow or shoulder abduction occurs (arm is immediately abducted, or elbow flexes at start of motion) - (1) – Elbow flexion or shoulder abduction occurs during shoulder flexion (in later phases of motion) - (2) - Performed faultlessly (patient can flex shoulder above, with forearm in mid- position and no elbow flexion) 5c. Pronation/supination of forearm, elbow at 0°, and shoulder at 30°-90° of flexion: •Subject is sitting with elbow extended, hand resting on knee. •Have participant perform movement with unaffected side first. 144 •Subject is instructed to pronate and supinate the forearm as the shoulder is flexed between 30- 90° and the elbow is fully extended. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – Supination and pronation cannot be performed at all, or elbow and shoulder positions cannot be attained - (1) – Elbow and shoulder properly positioned and supination performed in a limited range - (2) - Performed faultlessly (complete pronation and supination with correct positions at elbow and shoulder) VI. Normal Reflexes (sitting) (6) •ONLY DONE IF THE SUBJECT ATTAINS A SCORE OF 6 ON SECTION V (i.e., if the subject does not score a 2 on each of the 3 previous items, then score this item 0). •The examiner shall elicit biceps and triceps phasic reflexes with a reflex hammer and finger flexors with quick stretch to the affected arm and note if the reflexes are hyperactive or not. •Scoring (Maximum possible score = 2): - (0) - At least 2 of the 3 phasic reflexes are markedly hypractive - (1) – One reflex is markedly hyperactive or at least 2 reflexes are lively - (2) - No more than one reflex is lively, and none are hyperactive VII. Wrist (7a, 7b, 7c, 7d, 7e) The patient is asked to perform five separate movements: 7a. Stability, elbow at 90°, and shoulder at 0°: •Subject is sitting with arm and hand resting at side. •Have participant perform movement with unaffected side first. •Subject is instructed to dorsiflex (extend) the wrist to the full range of 15° (or full available range) with the elbow at 90° flexion and the shoulder at 0°. If full range of dorsiflexion is attained, slight resistance is given. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) - Patient cannot dorsiflex wrist to required 15° - (1) – Dorsiflexion is accomplished, but no resistance is taken - (2) - Position can be maintained with some (slight) resistance 7b. Flexion/extension, elbow at 90°, and shoulder at 0°: •Subject is sitting with arm and hand resting at side. •Have participant perform movement with unaffected side first. •Subject is instructed to perform repeated smooth alternating movements from 15 degrees of dorsiflexion (wrist extension) to 15 degrees of volar flexion with the fingers somewhat flexed. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) - Volitional movement does not occur 145 - (1) – Patient cannot actively move through the wrist joint throughout the total range of motion - (2) – Faultless, smooth movement (repetitive through full available ROM) 7c. Stability, elbow at 0°, and shoulder at 30° flexion: •Subject is sitting with elbow extended, hand resting on knee and forearm pronated. •Have participant perform movement with unaffected side first. •Subject is instructed to dorsiflex (extend) the wrist to the full range of 15° (or full available range) with the elbow fully extended and the shoulder at 30° flexion. If full range of dorsiflexion is attained, slight resistance is given. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) - Patient cannot dorsiflex wrist to required 15° - (1) – Dorsiflexion is accomplished, but no resistance is taken - (2) - Position can be maintained with some (slight) resistance 7d. Flexion/extension, elbow at 0°, and shoulder at 30° flexion: •Subject is sitting with elbow extended, hand resting on knee and forearm pronated. •Have participant perform movement with unaffected side first. •Subject is instructed to perform repeated smooth alternating movements from maximum dorsiflexion to maximum volar flexion with the fingers somewhat flexed to the full range of 15° (or full available range) with the elbow fully extended and the shoulder at 30° flex. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) - Volitional movement does not occur - (1) – Patient cannot actively move throughout the total range of motion; - (2) – Faultlessly, smooth movement (repetitive through full ROM) 7e. Circumduction: •Subject is sitting with arm at side elbow flexed to 90°, and forearm pronated. •Have participant perform movement with unaffected side first. Subject is instructed to circumduct the wrist with smooth alternating movements throughout the full range of circumduction. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – Cannot be performed (volitional movement does not occur) - (1) – Jerky motion or incomplete circumduction - (2) – Complete motion with smoothness (performs faultlessly, smooth, repetitive movement through full ROM) VIII. Hand (8a, 8b, 8c, 8d, 8e, 8f, 8g) The patient is asked to perform seven separate movements: 8a. Finger mass flexion: 146 •Subject is sitting with arm on bedside table or lap. •Have participant perform movement with unaffected side first. •Starting from the position of finger extension (this may be attained passively if necessary), instruct the patient to fully flex all fingers. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): • (0) – No flexion occurs • (1) – Some flexion, but not full motion • (2) – Completed active flexion (compared to unaffected hand) 8b. Finger mass extension: •Subject is sitting with arm on bedside table or lap. •Have participant perform movement with unaffected side first. •Starting from the position of finger flexion (this may be attained passively if necessary), instruct the patient to fully extend all fingers. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – No extension occurs - (1) – Patient can release an active mass flexion grasp - (2) – Full active extension (compared to unaffected side) 8c. Grasp I: •Subject is sitting with arm on bedside table. •Have participant perform movement with unaffected side first. •Instruct the patient to extend the metacarpophalangeal joints of digits II-V and flex the proximal & distal interphalangeal joints. Test this grip against resistance. You can tell the patient “pretend you are holding the handle of a briefcase.” •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – Required position cannot be attained - (1) – Grasp is weak - (2) – Grasp can be maintained against relatively great resistance 8d. Grasp II: •Subject is sitting with arm on bedside table. •Have participant perform movement with unaffected side first. •Instruct the patient to abduct the thumb to grasp a piece of paper (tester may insert the paper). Then ask the participant to perform pure thumb adduction with the scrap of paper interposed between the thumb and first digit (as in figure). Test this grip against resistance by asking the patient to hold as you attempt to pull the paper out with a slight tug. 147 •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – Function cannot be performed - (1) – Scrap of paper interposed between the thumb and index finger can be kept in place, but not against a slight tug - (2) – Paper is held firmly against a tug 8e. Grasp III: •Subject is sitting with arm on bedside table. •Have participant perform movement with unaffected side first. •Instruct the participant to grasp a pen by opposing the thumb and index finger pads around the pencil. The tester may support the participant’s arm but may not assist with the hand function required for the retrieval task. The pen may not be stabilized by the therapist or the participant’s other hand. To minimize excessive movement, however, a pen with a ‘pocket clip’ that prevents rolling more than 180° may be used. •Once the pencil is retrieved, instruct the patient to oppose the thumb pad against the pad of the index finger with a pencil interposed. Test this grip against resistance by asking the patient to hold as you attempt to pull the pencil out with a slight tug. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) – Function cannot be performed - (1) – A pencil interposed between the thumb pad and the pad of the index finger can be kept in place, but not against a slight tug - (2) – Pencil is held firmly against a tug 8f. Grasp IV: •Subject is sitting with arm on bedside table. •Have participant perform movement with unaffected side first. •Instruct the patient to grasp a small can (placed upright on a table without stabilization) by opening the fingers and opposing the volar surfaces of the thumb and digits. The arm may be supported but the tester may not assist with hand function. •Once the can is grasped, test this grip against resistance by asking the patient to hold as you attempt to pull the can out with a slight tug. Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) Function cannot be performed - (1) – A can interposed between the thumb and index finger can be kept in place, but not against a slight tug - (2) – Can is held firmly against a tug NOTE: the hand must open and close on the can; it is not acceptable to have the patient grasp can by coming down from the top of the can. 8g. Grasp V: 148 •Subject is sitting with arm on bedside table. •Have participant perform movement with unaffected side first. •Instruct the patient to perform a spherical grasp by grasping a tennis ball. The tester may support the participant’s arm but may not assist with the hand function required for the retrieval task. The ball may not be stabilized by the therapist or the participant’s other hand. To minimize excessive movement, the ball can be placed on an object that reduces rolling. An inverted medium-sized bottle cap or other small ‘bowl’ shaped object that fits under the ball to prevent rolling is acceptable. (A Snappletype bottle’s cap works well)..Once the tennis ball is grasped, test this grip against resistance by asking the patient to hold as you attempt to pull the ball out with a slight tug. •Test 3x on the affected side and score best movement. •Scoring (Maximum possible score = 2): - (0) Function cannot be performed - (1) – A tennis ball can be kept in place with a spherical grasp, but not against a slight tug - (2) – Tennis ball is held firmly against a tug IX.Coordination/speed - Sitting: Finger to nose (5 repetitions in rapid succession) (9a, 9b, 9c) •Subject positioned in sitting with eyes open. •Have participant perform movement with unaffected side first. •Subject is instructed to "bring your finger from your knee to your nose, as fast as possible." •Use a stopwatch to time how long it takes the subject to do 5 repetitions. •Repeat the same movement with the affected arm. Record the time for both the unaffected and affected sides. Observe for evidence of tremor or dysmetria during the movement. •Scoring Tremor (Maximum possible score = 2): - (0) - Marked tremor - (1) – Slight tremor - (2) – No tremor •Scoring Dysmetria (Maximum possible score = 2): - (0)- Pronounced or unsystematic dysmetria - (1) – Slight or systematic dysmetria - (2) – No dysmetria •Scoring Speed (Maximum possible score = 2): - (0) – Activity is more than 6 seconds longer than unaffected hand - (1) – (2-5.9) seconds longer than unaffected side - (2) – less than 2 seconds difference •NOTE: This item attempts to discriminate between basal ganglia, thalamic, or cerebellar strokes in which tremor or dysmetria may result as a direct result of lesion to these areas. The majority of stroke cases are in the middle cerebral artery or basilar artery where we expect to observe paralysis that affects movement speed but does not cause tremor or dysmetria. In cases of complete paralysis, observe for any indication of tremor or dysmetria that may be evident in face, voice, arms or legs. If there are no indicators of tremor or dysmetria, then score these items 2 and score speed 0. 149 SENSORY ASSESSMENT a) Light touch: Procedure: •The procedure can be tested in the sitting or supine positions. Explain to the participant with their eyes open, “ I am going to touch you with this cotton ball and I would like you to tell me if you can feel that you are being touched.” Touch patient by sweeping a cotton ball over the unaffected muscle belly. Ask them, “Can you feel that you are being touched?” This part of the procedure confirms that the patient understands the test. •Explain to the participant, “I am going to ask you to close your eyes. Then I am going to touch you with the cotton ball on your right/left (unaffected) side followed by your right/left (affected) side. When I ask you, tell me if you can feel the touch.” Ask the participant to close their eyes. Sweep unaffected area with cotton ball and ask, “Do you feel this?” Sweep affected area with cotton ball and ask “Do you feel this?“ If the participant says they feel the touch on both sides, then repeat the procedure by touching first the unaffected side immediately followed by the affected side and ask the following question. “Does ‘this’ (unaffected area touch) feel the same as ‘this’ (affected area touch)?” The intent is to determine if there are differences in the characteristics of the touch between the two sides. •If the tester is not confident that the participant understands this procedure or that the response is inconsistent, the tester may confirm their impression by using the following procedure. With the eyes closed, touch the participant on the affected side and ask them to point to where they were touched with the unaffected side. If the participant does not recognize that they are being touched, the score would be absent. If they recognize the touch but are not accurate on the localization, the score will be impaired. If they recognize the touch and are accurate on the localization, the score will be intact. Upper Extremity (1a, 1b) Upper arm: Follow above procedure by touching participant over the unaffected and affected biceps muscle belly. Palmar surface of the hand: Follow above procedure by touching participant over the unaffected and affected palmar surface of the hand. Lower Extremity (1c, 1d) Thigh: Follow above procedure by touching participant over the unaffected and affected thigh of the leg. Sole of foot: Follow above procedure by touching participant over the unaffected and affected sole of the foot. Scoring : (0) – Absent - If the participant states that he does not feel the touch on the affected side, the score is absent. 150 (1) – Impaired - If the participant states that he feels the touch on the affected side and the touch does not feel the same between affected and unaffected sides or the response is delayed or unsure, the score is impaired. (2) – Intact - If the participant states that he feels the touch on the affected side and the touch feels the same between affected and unaffected sides, the score is intact. b) Proprioception: Upper Extremity (2a, 2b, 2c, 2d) Tests can be completed in the supine or sitting positions. Shoulder: Therapist supports participant’s arm by the medial and lateral epicondyles of the humerus and at the distal ulnar and radius. Have participant look at arm. Move shoulder, saying “This is up. This is down.” I am now going to have you close your eyes and I’m going to move your shoulder in either direction. I want you to tell me “up” or “down.” Randomly move arm approximately 10 degrees, 4 times (more if needed), keeping track of correct responses. Elbow: Therapist supports participant’s arm by the medial and lateral epicondyles and the distal ulnar and radius. Have participant look at elbow. Move elbow, saying “This is up. This is down.” I am now going to have you close your eyes and I’m going to move your elbow in either direction. I want you to tell me “up” or “down.” Randomly move elbow approximately 10 degrees, 4 times (more if needed) keeping track of correct responses. Wrist: Therapist supports participant’s wrist at the distal ulna and radius and the heads of the 2nd and 5th metacarpal. Have participant look at wrist. Move wrist, saying “This is up. This is down.” I am now going to have you close your eyes and I’m going to move your wrist in either direction. I want you to tell me “up” or “down.” Randomly move wrist approximately 10 degrees, 4 times (more if needed), keeping track of correct responses. Thumb: Therapist supports participant’s thumb proximal to the interphalangeal joint and either side of the most distal aspect of the thumb. Have participant look at thumb. Move thumb at interphalangeal joint, saying “This is up. This is down.” I am now going to have you close your eyes and I’m going to move your thumb in either direction. I want you to tell me “up” or “down.” Randomly move thumb approximately 10 degrees, 4 times (more if needed), keeping track of correct responses. Lower Extremity (2e, 2f, 2g, 2h) The hip and knee should be tested in the supine position. The ankle and toe can be tested in the supine or sitting position. Hip: Therapist supports participant’s leg at the femoral condyles and the medial and lateral malleolus. Have participant look at leg. Move hip, saying “This is up. This is down.” I am now going to have you close your eyes and I’m going to move your hip in either direction. I want you to tell me “up” or “down.” Randomly move hip approximately 10 degrees, 4 times (more if needed), keeping track of correct responses. 151 Knee: Therapist supports participant’s leg at the femoral condyles and the medial and lateral malleolus. Have participant look at knee. Move knee, saying “This is up. This is down.” I am now going to have you close your eyes and I’m going to move your knee in either direction. I want you to tell me “up” or “down.” Randomly move knee approximately 10 degrees, 4 times (more if needed), keeping track of correct responses. Ankle: Therapist supports participant’s leg at the medial and lateral malleoli and the heads of the 1st and 5th metatarsal. Have participant look at ankle. Move ankle, saying “This is up. This is down.” I am now going to have you close your eyes and I’m going to move your ankle in either direction. I want you to tell me “up” or “down.” Randomly move ankle approximately 10 degrees, 4 times (more if needed), keeping track of correct responses. Toe: Therapist supports participant’s toe at the interphalangeal joint and either side of the most distal aspect of the great toe. Have participant look at great toe. Move interphalangeal joint, saying “This is up. This is down.” I am now going to have you close your eyes and I’m going to move your big toe in either direction. I want you to tell me “up” or “down.” Randomly move great toe approximately 10 degrees, 4 times (more if needed), keeping track of correct responses. Scoring: (0) – Absent (no sensation) (1) – Impaired (three quarters of answers are correct, but considerable difference in sensation compared with unaffected side) (2) – Intact (all answers are correct, little or no difference). Adapted from: http://leaps.usc.edu/Portals/0/files/misc/Clinical_Outcome_Measures_and_Procedures/Fugl- Meyer_2009_1_29.pdf. Accessed on 11/27/10. 152 Fugl-Meyer Lower Extremity Examination Scoring: 0 = no motion 1 = partial motion 2 = full motion Affected Unaffected Test 1 Reflex activity (can reflexes be elicited or not?): supine 1. patellar 0=no reflex activity 0 2 0 2 2. Achilles 2=reflex activity elicited 0 2 0 2 Test 2 Dynamic movement within flexor synergy: supine 3. hip flexion 0 1 2 0 1 2 4. knee flexion 0 1 2 0 1 2 5. ankle dorsiflexion 0 1 2 0 1 2 Dynamic movement within extensor synergy: sidelying 6. hip extension 0 1 2 0 1 2 7. hip abduction 0 1 2 0 1 2 8. knee extension 0 1 2 0 1 2 9. ankle plantarflexion 0 1 2 0 1 2 Test 3 Active movement while sitting: o 10. flex knee to and past 90 0 1 2 0 1 2 11. ankle dorsiflexion 0 1 2 0 1 2 o actively flexed to about 90 Test 4 Active movementwhile standing: o 12. flex knee to 90 with hip at 0 0 1 2 0 1 2 13. dorsiflex ankle 0 1 2 0 1 2 Test 5 Normal reflex activity: seated 153 Fugl-Meyer Upper Extremity Examination Scoring: 0 = subject could not perform task at all 1 = subject could only perform task in part 2 = subject performed task faultlessly Test 1 Reflex activity (can reflexes be elicited or not?): Affected Unaffected 1. flexors 0 2 0 2 2. extensors 0 2 0 2 Test 2 Dynamic flexor synergy in the shoulder: 3. retraction 0 1 2 0 1 2 4. elevation 0 1 2 0 1 2 5. abduction 0 1 2 0 1 2 6. outward rotation 0 1 2 0 1 2 Dynamic flexor synergy in the elbow and forearm: 7. flexion 0 1 2 0 1 2 8. supination 0 1 2 0 1 2 Dynamic extensor synergy in the shoulder: 9. adduction and inward rotation 0 1 2 0 1 2 Dynamic extensor synergy in the elbow and forearm: 10. extension 0 1 2 0 1 2 11. pronation 0 1 2 0 1 2 Test 3 Motions with a mixture of the dynamic flexor and extensor synergies: 12. hand to lumbar spine 0 1 2 0 1 2 o 13. flexion of the shoulder from 0 to 90 0 1 2 0 1 2 14. pronation and supination of the forearm with the elbow 0 1 2 0 1 2 o actively flexed to about 90 154 Test 4 Volitional movements performed with little or no synergy dependence: o 15. shoulder abduction from 0-90 0 1 2 0 1 2 o 16. shoulder forward flexion from 90-180 0 1 2 0 1 2 17. pronation and supination of forearm with elbow straight 0 1 2 0 1 2 (shoulder slightly flexed) Test 5 Normal reflex activity: 18. scored as being hyperactive or not 0 2 0 2 Test 6 Three different functions of the wrist: o o 19. wrist stability (shoulder 0 ; elbow 90 ) 0 1 2 0 1 2 o o 20. wrist flexion/extension (shoulder 0 ; elbow 90 ) 0 1 2 0 1 2 o o 21. wrist stability (shoulder 30 ; elbow 0 ) 0 1 2 0 1 2 o o 22. wrist flexion/extension (shoulder 30 ; elbow 0 ) 0 1 2 0 1 2 23. circumduction of the wrist 0 1 2 0 1 2 Test 7 Seven details of function of the hand: 24. mass flexion of the fingers 0 1 2 0 1 2 25. mass extension of the fingers 0 1 2 0 1 2 26. grasp with extended metacarpophalangeal joints of 0 1 2 0 1 2 digits 2-5 and flexion of the proximal and distal interphalangeal joints 27. grasp with pure thumb adduction (scrap of paper 0 1 2 0 1 2 interposed between thumb and the 2nd metacarpal) 28. grasp with opposition of thumb pulpa against the 0 1 2 0 1 2 pulpa of the second finger (a pencil is interposed) 29. grasp a cylinder-shaped object 0 1 2 0 1 2 30. a spherical grasp (tennis ball) 0 1 2 0 1 2 Test 8 Co-ordination and speed: A finger-to-nose test is applied five times in succession, as rapidly as possible. 155 31. tremor 0 1 2 0 1 2 32. dysmetria 0 1 2 0 1 2 33. speed 0 1 2 0 1 2 TOTAL 156 Fugl-Meyer Sensory Examination The FMA-S contains 12 three-point items, 4 for light touch and 8 for position sense. The total score ranges from 0 to 24. The sensation for light touch is estimated subjectively. The patient is asked whether he or she feels that light touches on both arms, the palmar surface of the hands, both legs and the soles of the feet give the same qualitative and quantitative impressions. The position sense of the joints is tested for the interphalangeal joint of the thumb, the wrist, the elbow and the gleno-humeral joint. Very small alterations in the position are accomplished by the rater. The rater also takes care to place his hand and fingers so that qualities of sensation other than in the position sense of the joints do not confuse the patients. In the lower limb, position sense is tested for the great toe, the ankle joint, the knee and the hip. Light Touch 0 = anaesthesia 1 = hypaesthesia/dysaesthesia 2 = normaesthesia Left Right 1. Arm 0 1 2 0 1 2 2. Palmar aspect of hand 0 1 2 0 1 2 3. Leg 0 1 2 0 1 2 4. Plantar aspect of foot 0 1 2 0 1 2 Position Sense 0 = absence of sensation 1 = considerable difference in sensation compared with the joint on the unaffected side, but at least 3/4 of the answers are correct 2 = all answers correct, little or no difference comparing unaffected with affected limb Left Right 1. Shoulder 0 1 2 0 1 2 2. Elbow 0 1 2 0 1 2 3. Wrist 0 1 2 0 1 2 4. Thumb 0 1 2 0 1 2 5. Hip 0 1 2 0 1 2 6. Knee 0 1 2 0 1 2 7. Ankle 0 1 2 0 1 2 8. Toes 0 1 2 0 1 2 157 WMFT Functional Ability Rating Rules Adapted from University of Alabama with University of Southern California modifications 7/17/03 GENERAL RULES 1. Attempt = Complete stop, move in opposite direction, or lose contact with the object being manipulated. 2. You do not need to rate the less affected side. 3. The less affected side is not necessarily a 5/5. 4. If in doubt about how to rate the more affected side, the less affected may be used as a comparator, but cautiously. To follow are some guidelines: a. "Normal" for some people may involve what looks like compensatory movement strategies. b. Try to tease out what is compensatory (from stroke-related deficits) vs. pre-existing alternate movement patterns that are "normal" for that individual. The first would be down- graded, the latter would not. c. Comparing the more affected to the less affected side may aid you, but also keep in mind that someone may be using compensatory strategies when moving the less affected upper extremity secondary to inadequate stabilization from the contralateral more affected side. d. If the less affected side is limited by an orthopedic problem or has a PROM limitation, you need to know this. The evaluator should verbalize this. 5. If the evaluator does NOT comment that the task was done incorrectly, it should be assumed that the task was completed correctly (see also General Rule #10) 6. If tester repeats task for whatever reason, rater must grade the final attempt. If because of a filming error the final attempt is impossible to grade, then do not grade and flag it to be evaluated by “the committee” unless it is an obvious “1” or “2”. 7. If unable to see the beginning or end of a task, but feel that there is enough to be able to rate, then do not rate, but flag item to be rated by “the committee” unless it is an obvious “1” or “2”. 8. In considering, score #2 – a “change in position” refers to any postural or limb compensation utilized to assist the test (more affected) limb in completion of the task. 158 9. When in doubt, grade low. 10. If participant does not truly complete the task (e.g. thumb does not cross the line on extend elbow task) OR an incorrect grasp is used, but tester makes error and seems to give credit for completion of the task, then flag the item to be rated by “the committee”. 11. For any task for which the starting position is hands in lap, if participant bumps table with any part of the UE then a “3” is the highest score that can be given. 12. If there is a discrepancy between the quality of movement of shoulder and the quality of movement of the hand or elbow that leads to an indecision regarding the score of an item, then take into consideration the category of the task and which arm movements are described as the movement of concern for that task. 13. If a task is repeated more than 2 times due to PARTICIPANT PERFORMANCE ERRORS (including inability to follow instructions), then a “1” is given. 14. If task is repeated more than 2 times secondary to TESTER ERRORS then do not rate, but flag item to be rated by “the committee”. 15. If the time score given is 120+ (not 120), it may be assumed that the participant was not able to complete the task within the allowable time, and therefore, 1 (non-functional range) would be the highest FAS score attainable. 16. Rating panel will use tester verbalization describing grasp to assist with rating grasp tasks: Lift can (9), Lift pencil (10), Lift Paperclip (11) & Turn Key in Lock (15). 17. If "rate by the committee" is designated, enter as code -5, and summarize the reason you made this designation in the comments’ section. a. If "rate by the committee" is chosen, but you think that a rating is attainable, document as above and include your rating in the comments’ section. TASK SPECIFIC RULES 1. Forearm to Table (side) a. If participant bumps table with any part of the UE then a “3” is the highest score that can be given. b. FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision with which movements are performed. 2. Forearm to Box (side) a. If participant bumps table with any part of the UE then a “3” is the highest score that can be given. 159 b. FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision with which movements are performed. 3. Extend Elbow (side) a. If tester incorrectly has participant keep going until entire thumb is across the 40cm line-then rate FA based on when any part of the thumb first crosses the line. But, flag the item for “the committee” to review in order to check the time score. b. On extend elbow and extend elbow with weight task, use the criteria re: limited elbow extension, i.e. a “2” is assigned for no elbow extension or almost no elbow extension. c. If hand comes off the table, then a “3” is the highest score which can be given. d. FA scoring should take into account: i. the extent to which the head and trunk are maintained in normal alignment, ii. whether the elbow is extended, iii. whether the hand remains in contact with the table, and iv. the speed, fluidity, and precision with which movements are performed. e. The elbow can be lifted off the table. i. Also, some shoulder external rotation and abduction is necessary, but inadequate or excessive motions of this type should be noted. 4. Extend Elbow with Weight a. If tester incorrectly has participant keep going until entire thumb is across the 40cm line-then rate FA based on when the leading edge of the weight initially crosses the line. But, flag the item for “the committee” to review in order to check the time score. b. On extend elbow and extend elbow with weight task, use the criteria re: limited elbow extension, i.e. a “2” is assigned for no elbow extension or almost no elbow extension. c. If participant does not keep elbow on the table, then a “3” is the highest score that can be given. d. FA scoring should take into account: i. the extent to which the head and trunk are maintained in normal alignment ii. whether the forearm remains in contact with the weight, and iii. the speed, fluidity, and precision with which movements are performed. e. Some shoulder abduction is necessary, but inadequate or excessive motions of this type should be noted. f. If the forearm doesn’t remain in contact with the weight, a maximum score of 3 should be assigned. g. If accomplished with excessive compensatory trunk movement and/or very limited elbow extension, a maximum score of 2 should be assigned. 5. Hand to Table (front) a. If participant bumps table with any part of the UE then a “3” is the highest score that can be given. b. If participant’s hand completely misses the circle, then a “2” is the highest score that can be given. 160 c. FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision with which movements are performed. d. The final posture of the hand and fingers does not influence scoring as long as the heel of the hand is in contact with the table. 6. Hand to Box (front) a. If participant bumps box with any part of the UE then a “3” is the highest score that can be given. b. FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision with which movements are performed. c. The final posture of the hand and fingers does not influence scoring as long as the heel of the hand is in contact with the table. 7. Weight to Box a. Do not rate this item. 8. Reach and Retrieve a. If participant’s arm is in the incorrect starting position with the thumb in contact with the table and forearm supination is absent (unable to assume correct start position) rate the item as a “0”. i. If in doubt about the starting position (alignment of head & trunk, arm/hand position or placement of weight) and how to score the performance, flag the item to be rated by “the committee”. b. A “2” is assigned for no elbow flexion or very limited elbow flexion. c. If weight maintains contact with the forearm but motion is “jerky” or arm bounces then a “3” is the highest score that can be given. d. If arm motion completely stops during performance count each motion restart as an attempt. i. If there are more than 2 attempts for task completion then a “2” is the highest score that can be given. e. FA scoring should take into account: i. the extent to which the head and trunk are maintained in normal alignment, ii. whether the activity is performed by bending the elbow as opposed to using excessive upper arm or hand movements (i.e., swatting the weight with the hand), and iii. the speed, fluidity, and precision with which movements are performed. iv. If the participant’s forearm loses contact with the weight or pronates, a maximum FA score of 3 should be assigned. v. If the participant is unable to maintain the starting position without physical assistance, a zero is assigned and activity is not attempted. 9. Lift Can a. If participant bumps table with any part of the UE then a “3” is the highest score that can be given. b. If complete overhand grasp is used to lift can, then give it a “1”. c. A cylindrical grasp should be used. 161 i. If any deviation (e.g. index finger on top of can) from cylindrical grasp is used, a maximum of “2” should be assigned. ii. If the participant uses a complete overhand grasp, then score as a “1” (see rule above). d. FA scoring should take into account: i. the extent to which the head and trunk are maintained in normal alignment, ii. the directness of the trajectory to the mouth, and iii. the speed, fluidity, and precision with which movements are performed. 10. Lift Pencil a. If participant bumps table with any part of the UE then a “3” is the highest score that can be given. b. If participant slides the pencil away from the center of the table somewhat - they can still get a “5” if it looks “normal” otherwise. c. If participant slides the pencil over the edge of the table in order to pick it up then a “1” is assigned. d. FA scoring should take into account: i. the extent to which the head and trunk are maintained in normal alignment, ii. whether the appropriate grasp is used (3-jaw chuck grasp), and iii. the speed, fluidity, and precision with which movements are performed. e. A 3-jaw chuck grasp should be used. i. If another grasp is used, a maximum FA score of 2 should be assigned. f. Raters should take into account the participant’s control of the grasp. g. If the participant immediately drops the pencil, a maximum FA score of 3 should be assigned. 11. Lift Paperclip a. If participant bumps table with any part of the UE then a “3” is the highest score that can be given. b. If participant slides the paperclip away from the center of the table somewhat - they can still get a “5” if it looks “normal” otherwise. c. If participant slides the paperclip over the edge of the table in order to pick it up then a “1” is assigned. d. FA scoring should take into account: i. the extent to which the head and trunk are maintained in normal alignment ii. whether the appropriate grasp is used (pincer grasp), and iii. the speed, fluidity, and precision with which movements are performed. e. A pincer grasp should be used. i. If another grasp is used, a maximum FA score of 2 should be assigned. f. Raters should take into account the participant’s control of the grasp. If the participant immediately drops the paperclip, a maximum FA score of 3 should be assigned. 12. Stack Checkers a. If participant bumps table with any part of the UE then a “3” is the highest score that can be given. b. If there are more than 2 attempts on any single checker then a score of “2” is the highest score that can be given. 162 c. FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision with which movements are performed. d. The checkers do not need to be perfectly aligned; therefore, do not deduct rating points based on alignment of checkers. 13. Flip Cards a. If participant bumps table with any part of the UE then a “3” is the highest score that can be given. b. If there were more than 2 attempts on any single card then a score of “2” is the highest score that can be given. c. If the participant does not go towards supination at all, and does not perform task in a quick, easy and smooth manner then rate the item a “2”. d. If participant does not go towards supination at all, but task is performed with fingers to flip the card in a quick, easy and smooth manner then rate the item at least a “3”, unless there were more than 2 attempts on one of the cards. Then it would automatically be a “2”. e. If the cards are flipped with all finger dexterity and there is some supination motion, but not past neutral (e.g. from pronation to less pronation), compare to the other side with respect to amount of supination, speed, fluidity, dexterity, precision. Keep in mind, the cautions stated in General Rule #4. f. If participant flips all cards end to end (vertical), then do not score it and send it to “the committee”. g. FA scoring should take into account: i. the extent to which the head and trunk are maintained in normal alignment, ii. the extent the forearm supinates when turning the cards, iii. the dexterity of the fingers, and iv. the speed, fluidity, and precision with which movements are performed. h. If the participant makes more than 2 attempts on any card, a maximum FA score of 2 should be assigned. i. If the participant fails to flip all cards side to side, a maximum FA score of 3 should be assigned. 14. Grip Strength a. Do not score this item. 15. Turn Key in Lock a. If participant bumps table with any part of the UE then a “3” is the highest score that can be given. b. If incorrect grasp is used then a “2” is the highest score that can be given. If more them 2 attempts of grasp occurs at any time the highest score that can be given is a “2”. c. If participant goes past vertical stop position (i.e. loss of control), then a “3” is the highest score that can be given. d. FA scoring should take into account: i. the extent to which the head and trunk are maintained in normal alignment, ii. whether the appropriate grasp is used (a lateral pincher grip), 163 iii. whether the forearm moves into pronation and supination as the key is turned, and the speed, fluidity, and precision with which movements are performed. e. If the participant doesn’t turn the key in the correct sequence (i.e., turn the key to side being tested first), a maximum of 3 should be assigned for FA score. f. If a grasp other than a lateral pincer grasp is used, a maximum FA score of 3 should be assigned. 16. Fold Towel a. Rate the arm being tested, but you may use the contralateral limb as a gauge to assess fluidity, speed and precision. Take pre- morbid UE dominance into consideration. b. If participant bumps table with any part of the UE then a “3” is the highest score that can be given. c. If participant requires more than 2 attempts on either part of the folding (whole to half or half to quarter), then a “2” is the highest score that can be given. d. FA scoring should take into account: i. the extent to which the head and trunk are maintained in normal alignment, ii. the symmetry of the arms as they fold the towel for the first fold, and iii. the speed, fluidity, precision with which movements are performed. e. The ends of the towel do not need to be exactly aligned after the second fold, but ends of the towel need to be approximately aligned (within 1.5 inches). 17. Lift Basket a. If basket bumps table on way up, then a “4” is the highest score that can be given. b. If participant lets go of the basket handle and pushes the basket across the table by using some part of the basket other than the handle, then a “2” is the highest score that can be given. c. If a grasp is not used to lift the basket by the handle (e.g. lifted with forearm) then the highest score that can be given is a “2”. d. The task is demonstrated with the leading edge of the basket crossing the far edge of the bedside table. If other portions of the basket cross the far edge of the table first, then a “3” is the highest score that can be given. e. FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision with which movements are performed. f. If the participant moves out of the original foot position, a maximum FA score of 3 should be assigned. g. The task is demonstrated with the leading edge of the basket crossing the far edge of the bedside table first. If other portions of the basket cross the far edge first, a maximum FA score of 3 should be assigned. The task is demonstrated without rotating the trunk. If the participant significantly rotates their trunk during the task, a maximum FA score of 3 should be assigned. WMFT FUNCTIONAL ABILITY SCALE 0 – Does not attempt with upper extremity (UE) being tested. 164 1 – UE being tested does not participate functionally; however, attempt is made to use the UE. In unilateral tasks the UE not being tested may be used to move the UE being tested. 2 – UE being tested participates functionally, but requires assistance of the UE not being tested for minor readjustments or change of position, or requires more than two attempts to complete, or accomplishes very slowly. In bilateral tasks the UE being tested may serve only as a helper. 3 – UE being tested participates functionally, but movement is influenced to some degree by synergy or is performed slowly or with effort. 4 – UE being tested participates functionally; movement is close to normal*, but slightly slower; may lack precision, fine coordination or fluidity. 5 – UE being tested participates functionally; movement appears to be normal *. (*) For the determination of normal, the less-involved UE can be utilized as an available index for comparison, with pre-morbid UE dominance taken into consideration, but cautiously. To follow are some guidelines: 1. "Normal" for some people may involve what looks like compensatory movement strategies. 2. Try to tease out what is compensatory (from stroke-related deficits) vs. pre-existing alternate movement patterns that are "normal" for that individual. The first would be down- graded, the latter would not. 3. Comparing the more affected to the less affected side may aid you, but also keep in mind that someone may be using compensatory strategies when moving the less affected upper extremity secondary to inadequate stabilization from the contralateral more affected side. 4. If the less affected side is limited by an orthopedic problem or has a PROM limitation, you need to know this. The evaluator should verbalize this. Wolf Motor Function Test (WMFT) Blinded Evaluator Administration Manual Adapted for ICARE 2009 LIST OF TEST OBJECTS AND RELATED ITEMS FOR THE WMFT The test objects and related items for the WMFT are listed below in the order in which they are used. Tasks should be administered with the subject seated in a standard chair at an appropriately sized desk or table (except for task 17 – done in standing). A laminated template should be secured to the tabletop or desktop. The template should be taped flush to the front edge of the table/desk and can be removed after testing. Test objects • Box (cardboard) – 10-inches (25.4cm) height 165 • This represents approximate shoulder height for average adult • 8-inch (20.3cm) or 6-inch (15.2cm) box should be available for shorter individuals • Cuff weight – 1lb, with velcro strap • Cuff weight – 20lb, with removable weight inserts • Soft drink can – 12oz, unopened • Pencil -7-inch (17.78 cm) • Paper clip - 2-inch (5.08 cm) - colored and coated with plastic • Checkers – three checkers of standard size • Index cards – three cards of standard size o 3-inch (7.62 cm) x 5-inch (12.7 cm) • Dynamometer – standard grip strength • Lock and key o Secured to a board that is placed at a 45-degree angle. o Tumblers are set so the key moves through a 180-degree arc (only), with 90 degrees of that arc on either side of midline. • Standard dish towel o 25-inch (63.5 cm.) x 15-inch (38.10 cm.). • Plastic or wicker tote basket with handle approximately o Height: 15 inches (38.1 cm) o Width: 8.5 inches (21.6 cm) o Length: 14 inches (35.56 cm) Related items • Desk/table - standard height, approximately: o Height: 29-inches (73.5 cm) o Width: 54-inches (137cm) o Length: 30-inches (76 cm) • Straight back chair without armrests o seat height: 18-inches (45.7 cm) • Template to be taped flush to the desk/table top to indicate test object placement • Talcum/baby powder • Stopwatch INSTRUCTIONS TEMPLATE • In order to assure a standard placement of test objects, a template, entitled Wolf Motor Function Test adapted for ICARE 2009, should be taped to the desk so that its front edge is flush with the front edge of the desk. • The center of the template should be at the center of the desk. • The outline of each test object is traced on the template in the position in which it should be placed and further identified by corresponding task item numbers. 166 • For the ICARE trial, all templates are labeled and provided by University of Southern California. • Each Clinical Site will have a pre-established table for use in administering the WMFT, with the template already secured in the proper place. PARTICIPANT SEATING One of the following chair positions will be used for each of the task activities: • Chair Position (Side): Chair placed sideways to the table. Position a box lengthwise at the 14 cm line, in the Box #2 position (see template). Place the participant’s less affected forearm flat on the top of the box, with the wrist hanging over the edge. Height of box should be such that shoulder is in 90 degrees of abduction. With arm in this functional position, place chair so that the patient’s hips and back are against the back of the chair. (Note: make sure that the trunk is straight and Participant is not leaning to the side.) o Measure position from the table edge to the side edge of the chair seat and the position of the back of the chair seat to the end of the table. • Chair Position (Front): Chair is facing the table. Position a box at the 20 cm line, in the Box #6 & 7 position of the template. Place the Participant’s hand on the top of the box, with the heel of the hand past the front edge of the box; elbow is straight. Height of the box should be such that the shoulder is at 900 flexion. With the arm in this functional position, place the chair so that the participant’s hips and back are fully against the back of the chair. o Measure this position, from the back of the seat of the chair to the edge the table. • Chair Position (Front-Close): For use with item #8 &14. Chair is facing the table. Participant is centered to the midline of the template. Place the Participant’s neutral forearm on the table, with the wrist crease at the 40-cm line and the elbow straight. With the arm in this functional position, place the chair so that the Participant’s hips and back are fully against the back of the chair. (Note: With larger participants, if the mass of the body does not allow for the wrist to reach the 40-cm line, the chair position should be such that the front of the body nearly touches the table, with the hips and back fully against the back of the chair. o Measure this position from the back of the chair seat to the table edge. • Note position measurements on the set-up recording form. Chair positions should be established using the unaffected upper extremity. VIDEOTAPING • All testing sessions should be videotaped for later rating by a panel of clinicians blinded to the pre- or post- treatment status of the participant or to other considerations that might bias rating. • A randomized accession number will be provided with the clinical recording forms. 167 • For each session, film the accession number before beginning the test. • Camera height and position should allow a field of view that includes maximal clarity of the task end position on the template. Additionally, one of the following filming positions should be used when videotaping each task. The specific task instructions indicate which filming position to use. Filming position (Side-Facing) – View of the whole body while participant’s side being tested is placed next to the desk: The camera should be placed approximately 3 feet in front of and to the opposite side of the participant being tested (camera on participant’s left side if right arm being tested) and in line with the back edge of the desk. The camera view should include the participant’s entire body so that the full movement of the hand from the lap to the table can be seen. Filming position (Side-Side) – View of the whole body while participant is facing the desk: The camera should be placed approximately 3 feet to the side of the participant and on the same side being tested (camera on participant’s left side if left arm being tested) and in line with the back edge of the desk. The camera view should include the participant’s entire body. Filming position (Side-Close) - Profile of Expanded View of Limb Being Tested. Camera in same position as Side-Side, but the camera view should be zoomed in to focus on fine motor skills. The view should include the participant’s entire upper extremity. Filming Position (Front) - Front View: The camera should be placed approximately 3 feet in front of the desk and the camera view should include the participant’s upper body (trunk and head). GENERAL COMMENTS • For all timed tasks, participants should be told to perform the tasks as quickly as possible. • Starting Point: The tester cues the start of the timed tasks by saying, “Ready! Set! Go!” This should be said quickly and vigorously. • Start time must be coincident with “GO!” The stop time must be coincident with the event defined in the instructions. • If the participant performs the task incorrectly, the task should be described and demonstrated again, and the participant is allowed one additional attempt. • If the blinded evaluator makes a mistake with set-up or timing, the task may be repeated an additional time. • Blinded Evaluator clearly states the reason when a task is repeated. • Blinded Evaluator clearly states if task was completed correctly. 168 • For the grasp items, verbalize the grasp utilities (digital positions), whether it is correct or incorrect. • Timing is carried out using a stopwatch that records to the millisecond. • Each task should be described and modeled two times by the tester at the time the instructions are given. The first demonstration should be conducted slowly, and the second should be performed quickly. • Both upper extremities are to be tested. First, the less-affected upper extremity should be tested on each task. The entire set of task should then be repeated with the more-affected upper extremity • Participants should not practice the task before being tested. • If the participant seems at all confused or has not paid attention during the demonstration, the task should be demonstrated a third time. • Testing should be performed at a desk that is approximately 54 inches (13-cm.) long, 30 inches (76-cm.) wide, and 29 inches (73.5-cm.) high. The testing room should be a minimum of 17 feet x 10 feet to allow adequate room for videotaping. • The chair position should be varied for participants who are substantially taller or shorter than 5’8”so that their starting position is optimal for task performance (e.g., desk doesn’t block/restrict movement, participant can reach objects). • A step may be placed beneath the participant’s feet to achieve proper lumbar, pelvic & hip alignment. • Final chair position should be established using the less-affected upper extremity. • For tasks using a box, shorter boxes may be substituted for shorter individuals. Ideally, these tasks should not require participants to flex or abduct their shoulder past 90 degrees. Modifications should be recorded on the pre-treatment set-up recording form and repeated during all subsequent testing of the participant. • Boxes with modified heights should not be used to accommodate range of motion limitations. If a participant is unable to perform a task because of range of motion limitations, the task should be considered unachievable for that participant and a 120+ assigned as the time score. • Verbal encouragement may be given to participants during the task attempts to maintain motivation or attention. The phrase “good effort, keep going, don’t give up” should be 169 repeated in a calm, confident voice. The phrase should be repeated approximately 12 times over the 2- minute period (i.e., once every 10 seconds). • If objects are dropped on the floor during a task attempt, the tester should quickly return the object to the starting position without interrupting the timing process. It may be helpful to have back-up items (i.e., extra paper clip, pencil, etc.) so that the item can be replaced quickly if dropped. If it takes longer than 5 seconds to replace an item, the task should be repeated. • If a participant appears confused or misunderstands the task, the task should be repeated. Entire verbal instructions and demonstration are repeated 1 time per task if the participant appears confused. If the participant performs the task incorrectly the second time, a 120+ is assigned for the time score. • Participants wearing long sleeves should roll the sleeve up on the arm to be tested before beginning the test. If participants are wearing a confining top and their sleeves cannot be rolled up, they should be asked to remove it and should be given a scrub suit top. • WMFT data collection and pre-treatment set-up recording forms are downloadable from the ICARE web-site. • The participant’s performance time is written on the data collection forms. The pre- treatment set-up form is used to note variations in chair position and test object during pre- treatment testing of the less-affected arm so that they may be replicated during other testing administrations. • The pre-treatment set-up recording form should be available during subsequent testing as a guide. • The previous data collection forms should not be viewed during subsequent testing administrations. • For each of the 17 tasks, a detailed instruction, with accompanying task demonstration is to be provided to the Participant followed by a brief instruction and accompanying demonstration. • For each task, the specific instructions are detailed on the following pages, along with set-up, filming, timing and scoring instructions. • Following the brief instruction, the Participant is to be asked if he/she has any questions. If the answer, is no, proceed with “Ready! Set! Go!” for all timed tasks. If the Participant has a 170 question(s), answer it and then repeat the brief instruction prior to proceeding with “Ready! Set! Go!” for all timed tasks. TEST ADMINISTRATION • Begin each test by reading the following to the Participant:: Today we are going to take a look at how you are able to use your arm. Let me tell you how we are going to go about this. First, I will give you instructions on how to do the task, and then I will show you how to do it. I will describe and demonstrate each task 2 times. Do not practice the task while I'm describing and demonstrating it; however, I will be happy to clarify any confusing points. Then I will say "Ready! Set! Go!" and you will do the task as quickly as you can. It is important that you do not start until I say "Go!"; otherwise, we will need to repeat the entire task. Each of the activities you will be asked to do should be carried out as rapidly as possible. You can work on each task for up to two minutes. Please attempt each part of the test even if you do not think that you can do it. If you are unable to carry out a task, then we will go on to the next one. Again, try to do each task as rapidly as possible. Do you have any questions?" INDIVIDUAL TASK INSTRUCTIONS I. Tasks (1 & 2) Functional ability of the shoulder of the involved upper extremity; tasks performed to the side of the participant (i.e., away from the midsagittal plane of the participant). Shoulder movement of abduction. 1. Forearm to table (side) SET UP Starting Position: • Chair Position (Side). • Hips against back of chair. • Hands in lap. • Both feet on floor. • Filming Position (Side- Facing). TASK 171 Task Description: Participant attempts to place forearm on the table (adjacent and parallel to front edge) by abduction at the shoulder. (Some shoulder flexion will probably also be necessary to get arm past the edge of table.) "Forearm" is defined as the wrist and elbow. The palmar surface of the hand need not be flat. Timing ends when both the forearm and hand touch the table. Timing Procedure: Starts on word "Go" and ends when participant's forearm and hand both touch the table in the required position. Measure: The time elapsed from the starting point to the moment the forearm and hand touch the table in the required fashion. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • "Place your forearm on the table as quickly as you can. Do it just like this. At the end of the movement, your forearm and hand should be touching the surface of the table. Do this as quickly as you can." Verbal instructions while demonstrating quickly: • "Place your forearm on the table as fast as you can. Like this. ” • "Do you have any questions?" • "Ready! Set! Go!" (said quickly and vigorously). Scoring: FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision with which movements are performed. 2. Forearm to box (side) SETUP Starting Position: • Chair Position (Side). • Hips against back of chair. 172 • Hand not being tested in lap. • Shoulder of tested arm abducted with the forearm pronated and placed flat on table with radial edge adjacent and parallel to front edge of table; wrist crease at 39-cm line (front edge of box). Palmar surface of hand need not to be flat. • Place a box of appropriate height in the template outline marked Box #2. Box should be wide enough that participants entire forearm and elbow can fit on the box. Box should be stabilized by evaluator during the trial. • Filming Position (Side- Facing). TASK Task Description: Participant attempts to place forearm (elbow to wrist) on the box by further abduction at the shoulder. (Again some shoulder flexion may be necessary to clear edge of box.) At the end, the forearm should be flat on the box with the hand drooping over the side edge of box. The hand and wrist must be drooping over the front edge of box. Timing Procedure: Starts on word “Go” and ends when participant’s forearm and elbow are flat on the box, wrist is beyond 2-cm. line and the hand is beyond the end of the box in a relaxed position. Measure: The time elapsed from starting point to the moment the forearm touches the top of the box in the required fashion with the hand drooping over the edge of the box. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • "Place your forearm on the box as quickly as you can. Do it just like this. At the end, your whole forearm should be flat and touching the surface of the box, with your hand and wrist drooping over the edge of the box. Your elbow must be completely on the surface of the box. Do this as quickly as you can." Verbal instructions while demonstrating quickly: • "Place your whole forearm on the box as fast as you can. Like this.” • "Do you have any questions?" • "Ready! Set! Go!" (said quickly and vigorously). Scoring: FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision 173 with which movements are performed. II. Tasks (3&4). Functional ability of the elbow of the involved upper extremity; movements performed to the side of the participant (i.e., away from the midsagittal plane). Elbow movements of extension. (A small amount of external rotation at shoulder is a necessary component of these two tasks, but elbow extension is the primary component.) 3. Extend elbow (to the side) SET UP Starting Position: • Chair Position (Side). • Hips against back of chair. • Table surface should be lightly dusted with baby/talcum powder. • Hand not being tested in lap. • Shoulder of test arm abducted with forearm resting flat on table in a pronated position. Palmar surface of hand need not be flat on table. • Forearm being tested is resting on, adjacent and parallel to front edge of table; elbow at 14- cm line. • Filming Position (Side-Facing). TASK Task description: Participant attempts to reach across the 40-cm. line on template by extending the elbow (to the side). Elbow can be lifted off the table during the task. This may be the only way shorter subjects can reach 40-cm. line. Shoulders should be kept level to prevent leaning with the trunk. Some external rotation at the shoulder is necessary to carry out this movement, but the examiner should prevent too much of this movement. Timing Procedure: Starts on the word “Go” and ends when any part of the thumb crosses the line. Measure: The time elapsed from the starting point to the time any part of the thumb initially crosses the line. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • "Slide your hand across the table by moving your hand away from your body and straighten your elbow to its fullest extent; like this. Your thumb should cross this line (point to the 40-cm line). You can raise your elbow from the table if you like. Also, please keep your 174 shoulders level and just move your arm; just like this (demonstrate). Do not lean over; keep your body as straight as possible. Do this as quickly as you can." • (Note: the participant should slide his/her hand across the table. Repeat the task if the hand is lifted off of the table.) Verbal instructions while demonstrating quickly: • “Straighten your elbow as fast as you can. Slide your hand across the table so your thumb crosses this line (point to 40cm line)” • "Do you have any questions?" "Ready! Set! Go!" (said quickly and vigorously). Scoring: • FA scoring should take into account: 1) the extent to which the head and trunk are maintained in normal alignment, 2) whether the elbow is extended, 3) whether the hand remains in contact with the table, and 4) the speed, fluidity, and precision with which movements are performed. • The elbow can be lifted off the table. Also, some shoulder external rotation and abduction is necessary, but inadequate or excessive motions of this type should be noted. 4. Extend elbow (to the side) - with weight SET UP Starting Position: • Chair Position (Side). • Hips against back of chair. • Hand not being tested in lap. • Shoulder of test arm abducted with forearm resting flat on table in pronated position exactly as in last task. • Forearm of arm to be tested resting on, adjacent and parallel to front edge of table; elbow at 14-cm line; palmar surface of hand need not be flat. • 1 lb. weight placed at ulnar edge of wrist; distal end of the weight is aligned with ulnar styloid process (i.e., the weight is only touching the forearm). • Filming Position (Side-Facing). TASK Task description: Participant attempts to push the weight across the 40-cm. line by extending the elbow and (to a lesser extent) externally rotating shoulder. Elbow should be kept on the table throughout the task (different from the previous task), and shoulders should be kept level to prevent leaning with the trunk. Again, the examiner needs to be aware of participant's trunk leaning and/or 175 excessive external rotation at the shoulder to perform task (especially true for taller men). Note: the weight is to remain in contact with the forearm throughout the task. Repeat the task if the subject swats the weight. Timing Procedure: Starts on the word "Go" and ends when any part of the thumb crosses line. Measure: The time elapsed from the starting point to the time any part of the thumb initially crosses the line. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • "Push the weight across this line (point to 40-cm line) by moving your hand away from your body while trying to keep your elbow on the table; like this. Your forearm should remain in contact with the weight until your thumb crosses the line. Also, again, please keep your shoulders level and just move your arm, just like this (demonstrate). Do not lean over; keep your body straight. Do this as quickly as you can." Verbal instructions while demonstrating quickly: • "While your elbow is resting on the table, straighten your arm - pushing the weight until your thumb crosses this line (point to 40-cm line) as fast as you can; like this.” • "Do you have any questions?" • "Ready! Set! Go!" (said quickly and vigorously). Scoring: • FA scoring should take into account: 1) the extent to which the head and trunk are maintained in normal alignment, 2) whether the forearm remains in contact with the weight, and 3) the speed, fluidity, and precision with which movements are performed. • Some shoulder abduction is necessary, but inadequate or excessive motions of this type should be noted. • If the forearm doesn’t remain in contact with the weight, a maximum score of 3 should be assigned. • If accomplished with excessive compensatory trunk movement and/or very limited elbow extension, a maximum score of 2 should be assigned. III. Three Tasks (5,6,&7). Functional ability of the shoulder of the involved upper extremity; performed to the front of the participant. 176 5. Hand to table (front) SET UP Starting Position: • Chair Position (Front). • Both hands in lap. • Hips against back of chair. • Participant positioned so that leaning is not necessary to comfortably reach the table. • Filming Position(Side-Side). TASK Task Description: Participant attempts to place hand being tested on the table. The heel of the hand must rest beyond the 2 cm. line. The palmar surface of the hand need not be flat. (The subject should place most of the hand in the circle.) Timing Procedure: Starts on the word "Go" and ends when the heel of the hand and fingers touch table beyond the 2-cm. line. Measure: The time elapsed from starting point to moment the heel of the hand and fingers touch table beyond 2 cm. line. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • "Place your hand on the table so that the heel of your hand is beyond this line (point to 2-cm. line.) Most of your hand should be placed in the circle (demonstrate); like this. Your hand does not need to be flat. Do this as quickly as you can.” Verbal instructions while demonstrating quickly: • "Place your hand on the table in this circle (point to circle) as fast as you can” • "Do you have any questions?" • "Ready! Set! Go!" (said quickly and vigorously). Scoring: 177 • FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision with which movements are performed. • Note: The final posture of the hand and fingers does not influence scoring as long as the heel of the hand is in contact with the table. SET UP Starting position: • Chair Position (Front). • Hips against back of chair. • Hand not being tested in lap. • Hand to be tested placed on table, heel of hand just beyond the 2 cm. line. (i.e., just past line, in circle - as in final position on last task). • Box centered on table; front edge aligned with 20-cm. line. Box should be stabilized by someone during the trial. • Filming Position(Side-Side). TASK Task Description: Participant attempts to place hand on the box. The heel of the hand must be placed past the front edge of box. The palmar surface of the hand need not be flat. Timing Procedure: Starts on the word "Go" and ends when the heel of hand and fingers touch the box past the front edge of box. Measure: The time elapsed from starting point to moment the heel of hand and fingers touch box past the edge of the box. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • "Lift your hand from the table and place it on the box so that the heel of your hand goes past the edge of the box; like this. Do this as quickly as you can." Verbal instructions while demonstrating quickly: • "Place your hand on the box as fast as you can." 178 • "Do you have any questions?" • "Ready! Set! Go!" (said quickly and vigorously). Scoring: • FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision with which movements are performed. • Note: The final posture of the hand and fingers does not interfere with scoring as long as the heel of the hand and fingers are in contact with the box. SETUP Starting Position: • Chair Position (Front). • Hips against back of chair. • Hands not to be tested in lap. • Heel of hand to be tested placed on table just beyond 2-cm. line. • Cuff weight(s) in place around forearm to be tested; stacking of weights begun just distal to the elbow. The weights should be stacked while arm to be tested is resting on the table to avoid fatiguing the arm. • Participant’s hand should be placed on the table in the circle on the template with elbow off the table. Cuff weight should be unsupported. If the participant is unable to maintain the hand flat in the circle with the weight unsupported, a lighter weight should be tried until they are able to achieve the correct starting position i.e. with weight unsupported. • Cuff weights with 1-lb. inserts are preferable. • Box centered on table; front edge aligned with 20-cm. line. Box should be stabilized by someone during the trial. • Not Filmed. TASK Task Description: Participant attempts to place the (weighted) hand being tested on the box so that the heel of hand rests beyond the front edge of the box. Participant should not be permitted to lean in and use the body to help lift the weight; the entire back should remain in contact with the chair (scapular protraction of the moving UE is allowed). Tester must, place their finger behind the subject’s back at the top of the chair to determine if the subject’s back moves away from the chair. In stacking the weights near wrist, be sure to leave enough room for weights to clear the table. Timing Procedure: Not applicable. Measure: 179 • Amount of weight participant is able to lift to the box while keeping his/her back against the chair (not timed as previous tasks). • Weight amounts in the order attempted should be recorded. The maximum amount of weight lifted should be documented on the EF3a (WMFT Set-up Form) for use at subsequent evaluations. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • "Place your hand on the box so that the heel of your hand is beyond the front edge of the box (demonstrate); like this. Keep your back against the chair. That is very important. Take your time. You do not need to hurry." Verbal instructions while demonstrating slowly: • "Lifting this weight on your arm, place your hand on the box.” • "Do you have any questions?" • “When you are ready, place your hand on the box.” Special Considerations: • For the initial trial, the examiner should subjectively determine the appropriate starting weight by resisting the participant's attempt to hold the elbow extended, shoulder flexed to 900. The stronger the participant appears, the higher the initial weight should be. If participant is weak, task should begin with lower initial weight. Increases in the amount of 2 lbs. should continue until the participant's maximum or 20 lbs. is reached. When the participant has reached his/her apparent maximum, the next trial should be one lb. less. If that weight can be lifted, it is recorded as the maximum. A 2- minute rest period should be allowed after every three trials. • For follow up evaluations, starting weight should be the 80% of the maximum weight recorded from previous evaluation. This information will be documented on the EF3a form. • State amount of weight lifted for each trial. IV. One Task (8). Functional ability of the elbow of the involved upper extremity; performed to the front of the participant. 8. Reach and retrieve SET UP Starting Position: • Chair Position (Front- Close). 180 • Hips against back of chair. • Re-powder table. • 1 lb. weight centered on table and positioned just beyond 40-cm. line. • Hand not being tested in lap. • Elbow of arm to be tested extended, forearm in mid- position of pronation and supination and palm of hand in contact with weight. • The subject must be able to maintain the starting position while the tester states "Ready! Set! Go!" • Filming Position (Side-Side). TASK Task Description: Participant attempts to pull 1 lb. weight across the 8-cm. line. Task object is a cuff weight folded so that it is approximately 7.6-cm. (3") on each side, and kept in place by a velcro fastener. Assign a 120+ if the participant cannot attain the starting position. Timing Procedure: Starts on the word "Go" and ends when any part of the weight crosses the 8-cm. line. Measure: The amount of time elapsed from the starting point to the moment the leading edge of the weight crosses the 8-cm line. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • "Slide the weight across the table toward you until it is past this 8-cm line (point to red line). Do the task entirely by bending your elbow and keeping your thumb facing the ceiling (demonstrate); like this. The weight should remain in contact with your hand until it crosses this line (point to red line). Do this as quickly as you can." Verbal instructions while demonstrating quickly: • “Bend your elbow with your thumb facing up, sliding the weight across the table as fast as you can.” • "Do you have any questions?" • "Ready! Set! Go!" (said quickly and vigorously). Scoring: • FA scoring should take into account: 1) the extent to which the head and trunk are maintained in normal alignment, 2) whether the activity is performed by bending the elbow as 181 opposed to using excessive upper arm or hand movements (i.e., swatting the weight with the hand), and 3) the speed, fluidity, and precision with which movements are performed. • If the participant’s forearm loses contact with the weight or pronates, a maximum FA score of 3 should be assigned. • If the participant is unable to maintain the starting position without physical assistance, a zero is assigned and activity is not attempted. V. Nine Tasks (9-17). Functional ability of the arm and hand of the involved upper extremity; performed to the front of the participant. 9. Lift can SET UP Starting Position: • Chair Position (Front). • Hips against back of chair. • Hands in lap. • Unopened 12-oz. soft drink can (392 gm) placed on table at participant’s midline with front edge of can just beyond 20-cm. line. • Filming Position (Side- Close). TASK Task Description: Participant attempts to lift the can and bring it close to lips with a cylindrical grasp. An overhand grasp is not allowed for this task. Note - If the participant performs the task by lifting the can using an overhand grasp, repeat the task one more time. Assign a 120+ if the task is completed with an overhand grasp. Timing Procedure: Starts on the word "Go" and ends when can is within approximately one inch of participant's mouth. Measure: The time elapsed from starting point to the moment the can comes within approximately one inch of participant's mouth. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: 182 • "Lift the can to your mouth without touching your lips; like this (demonstrate). It is important that you use the appropriate grasp and an overhand grasp is not allowed (demonstrate both grasps). Do this as quickly as you can." Verbal instructions while demonstrating quickly: • "Lift the can to your mouth as fast as you can” • "Do you have any questions?" • "Ready! Set! Go!" (said quickly and vigorously). Scoring: • FA scoring should take into account: 1) the extent to which the head and trunk are maintained in normal alignment, 2) the directness of the trajectory to the mouth, and 3) the speed, fluidity, and precision with which movements are performed. SET UP Starting Position: • Chair Position (Front). • Hips against back of chair. • Hands in lap. • 7" pencil (with 6 flat sides) placed parallel to front edge of table, centered on participant's midline and with front edge of pencil at 20-cm. line. • Filming Position (Side- Close). TASK Task Description: Participant attempts to pick up the pencil using 3-jaw chuck grasp (thumb and first two fingers). The pencil should be picked up on the table and not over the edge of the table. Note - If the participant performs the task by lifting the pencil over the edge of the table once, repeat the task one more time. Assign a 120+ if the task is completed by bringing the pencil over the edge of the table. **Encourage the participant to use a 3-jaw chuck grasp. Timing Procedure: Starts on the word "Go" and ends when entire pencil (all surfaces) is raised from table at least ½ inch. Evaluator should be positioned at eye level with the tabletop. Evaluator should verbalize the grasp used, whether it is correct 3-jaw chuck grasp, or another grasp. 183 Measure: The time elapsed from the starting point to the moment the entire pencil is raised from the table. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • "Pick up the pencil using your thumb and first two fingers and hold it in the air like this (demonstrate). The pencil should be picked up on the table and not over the edge of the table. Do this as quickly as possible." Verbal instructions while demonstrating quickly: • "Pick up the pencil as fast as you can.” • "Do you have any questions?" • "Ready! Set! Go!" (said quickly and vigorously). Scoring: • FA scoring should take into account: 1) the extent to which the head and trunk are maintained in normal alignment, 2) whether the appropriate grasp is used (3-jaw chuck grasp), and 3) the speed, fluidity, and precision with which movements are performed. • A 3-jaw chuck grasp should be used. If another grasp is used, a maximum FA score of 2 should be assigned. • Raters should take into account the participant’s control of the grasp. If the participant immediately drops the pencil, a maximum FA score of 3 should be assigned. SET-UP Starting Position: • Chair Position (Front). • Hips against back of chair. • Hands in lap. • 2" paper clip (coated and colored) placed parallel to the edge of the table, centered on participant's midline, and with front edge of clip at 20-cm. line; the wider end of the paper clip should be facing towards the side to be tested. Filming Position (Side- Close). TASK Task Description: 184 Participant attempts to pick up the paper clip using a pincer grasp (pads of thumb and index finger opposed). The paper clip should be picked up on the table and not over the edge of the table. Note - If the participant performs the task by lifting the paper clip over the edge of the table once, repeat the task one more time. Assign a 120+ if the task is completed by bringing the clip over the edge of the table. **Encourage the participant to use a pincer grasp. Timing Procedure: Starts on the word "Go" and ends when entire paper clip is off the table at least ½ inch. Evaluator should be positioned at eye level with the tabletop. Evaluator should verbalize the grasp used, whether it is correct pincer, or another grasp. Measure: The time elapsed from the starting point to the moment the entire paper clip is raised from the table. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • "Pick up the paper clip using your thumb and index finger and hold it in the air like this (demonstrate). The paper clip should be picked up on the table and not over the edge of the table. Do this as quickly as possible." Verbal instructions while demonstrating quickly: • "Pick up the paper clip as fast as you can. • "Do you have any questions?" • "Ready! Set! Go!" (said quickly and vigorously). Special Consideration: Fingernail length can significantly affect performance; therefore, participant should be instructed during the phone call making test arrangements to not clip fingernails for at least three days before test session. Scoring: • FA scoring should take into account: 1) the extent to which the head and trunk are maintained in normal alignment, 2) whether the appropriate grasp is used (pincer grasp), and 3) the speed, fluidity, and precision with which movements are performed. • A pincer grasp should be used. If another grasp is used, a maximum FA score of 2 should be assigned. • Raters should take into account the participant’s control of the grasp. If the participant immediately drops the paperclip, a maximum FA score of 3 should be assigned. 185 SET UP Starting Position: • Chair Position (Front). • Hips against back of chair. • Hands in lap. • Three checkers are placed in a line parallel to front edge of table with front edge of each checker just beyond 20-cm. line (see circle outlines on template). Checkers are spaced 4.5-cm. apart with middle checker at participant's midline. • Filming Position (Side- close). TASK Task Description: Participant attempts to stack the two end checkers onto the center checker. The task can be executed by picking up either checker first. Timing Procedure: Starts on the word "Go" and ends when participant has placed the third checker in required position. Measure: The time elapsed from the starting point to the moment the third checker is in place. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • "Stack the two end checkers onto the center checker. The checkers do not have to be perfectly stacked, but the top two checkers must not touch the table surface. Do it like this (demonstrate correct method), not like this (demonstrate incorrect method of at least one checker still touching the table surface in the stacked position. See special consideration). Do this as quickly as you can." Verbal instructions while demonstrating quickly: • "Stack the two end checkers onto the center checker as fast as you can.” • "Do you have any questions?" • "Ready! Set! Go!" (said quickly and vigorously). Special Considerations: 186 Checkers may be out of alignment, but in order for the task to be considered completed, the top two checkers may not be touching the table surface. The tester should demonstrate what is not acceptable. Scoring: • FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision with which movements are performed. • The checkers do not need to be perfectly aligned; therefore, do not deduct rating points based on alignment of checkers. SET-UP Starting Position: • Chair Position (Front). • Hips against back of chair. • Hands in lap. • Three 3"x5" index cards placed in a line parallel to front edge of table, with short (3") far edge of card facing participant just beyond 20-cm. line. Cards spaced 3-cm. apart with middle card at participant's midline. • Filming Position (Side-Close). TASK Task Description: Using a pincer grasp on the near edge of cards, participant attempts to flip each of the cards over. This task should be done by sliding the front edge of the card just past the front edge of the table with some or all of the fingers and then grasping the card edge protruding past the table edge between the palmar surfaces of thumb and index finger. Cards should be flipped over from side to side (rather than from front to end). Evaluator should emphasize supination/pronation in demo. The cards do not have to be straightened or adjusted after they have been turned over. The participant should first flip over the card on side being tested, then the center card, and then the card on the opposite side. Timing Procedure: Starts on the word "Go" and ends when participant has flipped all cards into a new position. Measure: The time elapsed from the starting point to the moment the third card has been flipped over and released onto the table. VERBAL INSTRUCTIONS 187 Verbal Instructions while demonstrating slowly: • "Flip each of the cards over. You should slide the card toward you so that it goes a little over the edge of the table. Start with the card on your (state side (R/L), to match side being tested) side, then the center card, and then the card on your (state opposite side (R/L) from above) side. The cards should be flipped over from side to side like this (demonstrate) rather than from end to end (demonstrate); not like this. You should turn your forearm over like this (demo supination) instead of just using your fingers to flip the card over. The cards may land anywhere on the table, so you do not need to straighten the cards after turning them over. Do the task as quickly as you can." Verbal instructions while demonstrating quickly: • "Flip each of the cards over, from side to side, as fast as you can.” • "Do you have any questions?" • "Ready! Set! Go!" (said quickly and vigorously). Scoring: • FA scoring should take into account: 1) the extent to which the head and trunk are maintained in normal alignment, 2) the extent the forearm supinates when turning the cards, 3) the dexterity of the fingers, and 4) the speed, fluidity, and precision with which movements are performed. • If the participant makes more than 2 attempts on any card, a maximum FA score of 2 should be assigned. • If the participant fails to flip all cards side to side, a maximum FA score of 3 should be assigned. SET UP Starting Position: • Chair Position (Front- Close). • Hand not to be tested on thigh. • Hips against back of the chair. • Upper extremity to be tested placed on table, olecranon process at front edge of table, forearm in neutral position, elbow flexed, shoulder slightly flexed and in 00 abduction. • The hand-held dynamometer is set on the second setting position. • Grip strength dynamometer placed in hand that is resting on the table. The tester or an assistant should stabilize the dynamometer for the participant from the front of the participant. • Not Filmed. TASK 188 Task Description: Participant attempts to grip the dynamometer with greatest grip strength possible. The test should be conducted 3 times with a 1- minute rest between trials. Timing Procedure: Not applicable. Measure: The mean of grip strength exerted (kg) on 3 trials. VERBAL INSTRUCTIONS Verbal Instructions: • "Squeeze the handle as far as you can for at least 3 seconds and then let go when I say “Release.” I will ask you to do this 3 times with a 1-minute rest between attempts." (repeat instructions) • "Do you have any questions?" • "Ready! Set! Go!" (said vigorously) SET UP Starting Position: • Chair Position (Front). • Hands placed on thighs. • Hips against back of chair. • Lock and key board is stabilized at a 45 degree angle, preventing board from moving when used by participant; board held parallel to front edge of table, just beyond 8-cm. line and centered on participant’s midline. • Filming Position (Side-Close) TASK Task Description: Using a lateral pincer grasp, participant attempts to move the key in the lock from the vertical position first to the side being tested, then to the opposite side and finally back to the vertical starting position. Tumblers of the lock are set so that the key moves through a 180- degree arc (only), with 90 degrees of that arc on either side of the midline. **Encourage participant to use lateral pincer grasp. Timing Procedure: Start on the word "Go". End when the key is in the starting position again. Measure: 189 The time elapsed from the starting point to the moment the key is returned to the starting position. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • “Grasp the key between your thumb and your forefinger (demonstrate lateral pincer grasp) like this and turn the key, first to the (state (R/L) side being tested) as far as the key will turn, then to the (state (R/L) opposite side) as far as the key will turn and finally return the key to the original vertical position. There is a stop on either side. Be sure you move the key until you reach this point. Do this as quickly as you can.” Verbal instructions while demonstrating slowly: • “Turn the key in the lock, first to the (state (R/L) side being tested) and then to (state opposite side), then back to the middle, as fast as you can.” • “Do you have any questions?” • "Ready! Set! Go!" (said quickly and vigorously). Scoring: • FA scoring should take into account: 1) the extent to which the head and trunk are maintained in normal alignment, 2) whether the appropriate grasp is used (a lateral pincher grip), 3) whether the forearm moves into pronation and supination as the key is turned, and 4) the speed, fluidity, and precision with which movements are performed. • If the participant doesn’t turn the key in the correct sequence (i.e., turn the key to side being tested first), a maximum of 3 should be assigned for FA score. • If a grasp other than a lateral pincer grasp is used, a maximum FA score of 3 should be assigned. SET UP Starting Position: • Chair Position (Front). • Hands placed on thighs. • Hips against back of chair. • Face towel is placed flat on table centered on participant with front long edge of towel at 8-cm.line. • Filming Position (Side- Close) TASK Task Description: 190 Participant picks up the towel with both hands, grasping the far corners of the towel. The participant first folds the towel lengthwise. The participant then folds the towel in half again across its center (widthwise). The second fold is done with the arm being tested only and is done from the side of the towel corresponding to the arm being tested. The folding does not need to be exact, but ends of the towel need to be approximately aligned (within 1.5 inches). Timing Procedure: Starts on the word "Go" and ends when the towel is completely folded on the table. Measure: The time elapsed from the starting point to the moment the towel is completely folded on the table. VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • “Grasp the far corners of the towel and fold it lengthwise like this (demonstrate). Then fold it in half across its center by using your (state (R/L) the side being tested) arm. Try to get the ends of the towel close together (demonstrate). In order to complete the task, the ends of the towel must be close together. Do the task as rapidly as possible. Verbal instructions while demonstrating quickly: “Grasp the far corners of the towel and fold towards you, then fold in half using your (state (R/L) side being tested) hand as fast as you can.” • “Do you have any questions?” • "Ready! Set! Go!" (said quickly and vigorously). Scoring: • FA scoring should take into account: 1) the extent to which the head and trunk are maintained in normal alignment, 2) the symmetry of the arms as they fold the towel for the first fold, and 3) the speed, fluidity, and precision with which movements are performed. • The ends of the towel do not need to be exactly aligned after the second fold, but ends of the towel need to be approximately aligned (within 1.5 inches). SET UP Starting Position: 191 • Participant standing and facing table. • Bedside table is placed over the desk on the participant’s side to be tested. The table’s height is adjusted so that the Participant will not exceed 900 abduction, when the basket is placed on the table with the desired grasp. The bedside table extends along the width of the desk. • Basket at 8-cm. line, with leading edge at 14-cm. line on side to be tested, handles taped together & lined up with center of body. • Three-pound weight placed in basket. • Filming Position (Front). TASK Task Description: Participant attempts to pick up basket by grasping handle (from underneath the handle) and placing the basket on far edge of the rolling bedside table. The far edge of the basket should touch the far edge of the table. Timing Procedure: Starts on the word "Go" and ends when any portion of the base of the basket extends beyond the far edge of the bedside table. Measure: The time elapsed from the starting point to the moment the basket has been placed on the bedside table with any portion of the base of the basket beyond the far edge of the bedside table. (Note: release of the basket is not included in the time measure). VERBAL INSTRUCTIONS Verbal Instructions while demonstrating slowly: • “Pick up the basket with your (Right or Left) hand and place the basket on the table. The far edge of the basket should go past the far edge of the bedside table (demonstrate); like this. Try not to move your feet while you do this task. Do this as quickly as you can.” Verbal instructions while demonstrating quickly: • Pick up the basket with your (Right or Left) hand and place the basket on the table as fast as you can.” • “Do you have any questions?” • "Ready! Set! Go!" (said quickly and vigorously). Scoring: 192 • FA scoring should take into account the extent to which the head and trunk are maintained in normal alignment and the speed, fluidity, and precision with which movements are performed. • If the participant moves out of the original foot position, a maximum FA score of 3 should be assigned. • The task is demonstrated with the leading edge of the basket crossing the far edge of the bedside table first. If other portions of the basket cross the far edge first, a maximum FA score of 3 should be assigned. • The task is demonstrated without rotating the trunk. If the participant significantly rotates their trunk during the task, a maximum FA score of 3 should be assigned. Dose Optimization for Stroke Evaluation (DOSE) WOLF MOTOR FUNCTION TEST Task Times for More-affected Arm : (1=Right 2=Left) B1. Forearm to table Eval Date: Evaluator Initials: B2. Forearm to box ID number: Visit number: Accession number: (1-14) B3. Extend elbow B4. Extend elbow Task Times for Less-affected Arm: (1=Right 2=Left) A1. Forearm to table (side) A2.Forearm to box (side) A3. Extend elbow (side) A4. Extend elbow (weight) A5. Hand to table (front) A6. Hand to box (front) A7. Weight to box (front) a.Starting weight lbs b.Next trial lbs c.Next trial lbs d.Next trial lbs e.Next trial lbs f. Next trial lbs g.Next trial lbs h. Max trial lbs B5. Hand to table B6. Hand to box B7. Weight to box i. Starting weight lbs j. Next trial lbs k. Next trial lbs l. Next trial lbs m. Next trial lbs n. Next trial lbs o. Next trial lbs p. Max trial lbs B8. Reach and retrieve B9. Lift can B10. Lift pencil B11. Lift paper clip A8. Reach and retrieve (front-close) B12. Stack checkers 193 A9. Lift can (front) A10. Lift pencil (front) A11. Lift paper clip (front) A12. Stack checkers (front) A13. Flip cards (front) A14. Grip strength (front-close) a. 1st trial kgs b. 2nd trial kgs c. 3rd trial kgs A15. Turn key in lock (front) A16. Fold towel (front) A17. Lift basket (stand) B13. Flip cards B14. Grip strength d. 1st trial kgs e. 2nd trial kgs f. 3rd trial kgs B15. Turn key in lock B16. Fold towel B17. Lift basket C. General Comments (also account for missing data) Completed by: (sign) Initials: Date: DOSE : WMFT Pre-Treatment Set-Up Recording From Study ID: Evaluation Date: Arm tested: Less-affected (please circle one) Right/Left Visit #: Evaluator Initials: I. Chair Side-Facing Position: A. Position from the table edge to the side edge of the chair seat (cm): B. Position of the back of the chair set to black line on the side of the template (cm): C. Height of box (inch) II. Chair Front Position: A. Position from the back of chair seat to the edge of the table (cm): 194 B. Height of box (inch) III. Chair Front-Close Position: A. Position from the back of the chair seat to the table edge (cm): IV. Basket Task : Item #17 A. Table height (cm): V. Less-affected UE Max weight lifted for task 7 (lbs): VI. More-affected UE Max weight lifted for task7 (lbs): Additional Comments: 195 APPENDIX B: BRAIN SUITE ANALYSIS PROTOCOL Cerebrum Mask A. The first processing step for a subject’s MPRAGE scan is to create a cerebrum mask from the nifti (.nii.gz) file. 1. Create a separate folder for each subject. In order to prevent overwritten files/in case mistakes are made, create a new folder called “Edits” inside the subject folder. The “Edits” folder will contain all hand-edited files. Make sure that you have named your original .nii.gz file appropriately, as all files generated in this process will have the same filename beginning. 2. From the subject folder, open the original .nii.gz file in BrainSuite 15b. You should see 4 different views of the brain (coronal, sagittal, axial, 3D). 3. From the Cortex menu, select “Skull Stripping (BSE)” to determine good values to create your base mask. The default values will usually create a good base mask for you, but you should always check. Click “Apply” and close the window after the process has been run. If the automated mask comes out poorly, you can press the “back” button a few times to bring yourself back to the beginning of the skull stripping step and retry the process with adjusted parameters. Slightly altering these values may save you time on mask editing. a. Diffusion Iterations: “blurs” the scan to remove lines the computer might confuse for boundaries. Higher values will generally include more of the cortex if the scan has more blur. Adjust by a magnitude of +/- 1 each time. 196 b. Diffusion Constant: higher values will generally include more of the cortex. Adjust by a magnitude of +/- 5 each time. c. Edge constant: probably the best place to start. Higher values will generally include less of the cortex. Use this when there are thick lines in the scan. Adjust by a magnitude of +/- 0.01 each time. d. Erosion Size should always remain at 1. 4. Note the values chosen for the skull stripping process. You will need them for the Cortical Surface Extraction Sequence that will generate your cerebrum mask. 5. From the Cortex menu, select “Cortical Surface Extraction Sequence” and uncheck all steps after “Cerebrum labeling” (“Inner cortical mask” and on). If you followed the above steps and ran the skull stripping from the separate skull stripping window, then you should see that the skull stripping is already complete and the parameters you chose in the skull stripping window are already entered. (The separate skull stripping window you opened in step 3 has the advantage of a “back” button, which is not available in the “Cortical Extraction Sequence” window, and allowing you to run the step repeatedly until you are satisfied with the parameters.) 6. Click “stage” to progress through each of the checked processes. All of the files you are generating will appear in your working directory (i.e., the folder you created at the beginning from which you opened the original .nii.gz file) with the same filename beginnings. Note: BrainSuite saves over any files in your working directory when it 197 generates new files, including hand-edited files if you haven’t moved them to your “Edits” folder. This will be extremely important later on! 7. After the “Cerebrum labeling” process is finished, you can close the window and close BrainSuite. There should now be about 15 files in your folder, one of which should be named “[subject].cerebrum.mask.nii.gz” B. Once you have generated a raw cerebrum mask, you need to edit it to exclude anything that is not part of the cerebral cortex. 1. If you have not already done so, create an “Edits” subfolder in your subject folder, again to prevent overwritten files/in case mistakes are made. 2. Reopen the original .nii file in BrainSuite 15b. You should see the same 4 views of the brain. 3. Under the menus are icons. Click on the icon second to the left, “Image Display Properties.” A sidebar on the right should appear with 5 file fields. Your .nii.gz file should be in the field named “Volume.” You will want to place your cerebrum mask file into the field named “Mask.” 4. Drag your “[subject].cerebrum.mask.nii.gz” file to the “Mask” field. You should see the mask appear on your brain outlined in green. 5. Click on the “Coronal View” icon. You should edit the cerebrum mask primarily in the coronal view, going slice by slice anterior to posterior (or vice versa if you prefer). The coronal view gives you the best perspective of the sections of the brain we want to trace, though you will want to check your work in the sagittal view after you have completed your edit (more on this later). 198 6. Click on the “Mask Tool” icon, directly to the right of “Image Display Properties.” A different sidebar on the right should appear. In order to edit your mask, you have to check the box under “Mask Drawing” that says “edit mask” (straightforward enough). You will also need to hold down the control key. Lay something heavy on it, like your phone, so that you don’t have to hold it down yourself. 7. You need to use a physical mouse for tracing instead of a touchpad. Left-click includes; right-click excludes. Try clicking and dragging to see what happens. A simple control-Z undoes your most recent edit, like with any program. a. The green line is in. Anything that is inside or directly under the green line outlining your mask is included. b. To adjust image brightness (i.e., to help you differentiate between gray matter and non-gray matter), return to “Image Display Properties.” There are three vertical bars. Slide down the top black arrow of the left-most vertical bar to increase brightness. You can try manipulating brightness in other ways as well. c. To zoom in or out, hold down the alt key and click on the + or – key. To reposition your image, hold down the alt key and drag the image with your mouse. 8. In tracing your brain, you want to exclude: a. All meninges, the outer membrane that surrounds the brain and tends to resemble the color of gray matter. Thus BrainSuite gets confused and tends to include meninges in the cerebrum mask. 199 b. The cerebellum and brainstem. BrainSuite usually does a good job of leaving these out of the cerebrum mask, but be sure to trace a nice line outlining the inferior temporal region that excludes the cerebellum entirely. c. The optic tract, pons, and medulla. Whether you are starting your tracing in the anterior or posterior region, these will become apparent about midway through the brain. Make sure that you are tracing around these areas, and that your green outline runs through the third ventricle (the small hole in the middle of the brain within the thalamus). Again, BrainSuite tends to do this well, but be aware of the tracing procedure. 9. Save your work periodically! Click on the save icon in the Mask Tool panel and make sure you save your cerebrum mask in the Edits subfolder you created. Note on using the sagittal view for editing: Generally speaking, it’s best to only edit the mask in the coronal view. There are exceptions, however. At the very end, it’s good to check the very front and the very back in the sagittal view, since these areas are hard to edit in the coronal view. You should also use the sagittal view to exclude the membrane that separates the cerebrum and the cerebellum, which is also hard to see in the coronal view. 200 Full-Brain Mask In this step, we add the brainstem and the cerebellum to the cerebrum mask you edited in the previous step. We use the bottom of the cerebellum as a guide for how low the mask should go along the brainstem. Note that this criterion was decided midway through the processing of the second (year 3) scans, so earlier masks extend much further down the brainstem. 1. Open up your MPRAGE ([sbjID].nii.gz) from your main subject folder. Open up your “Edits” subfolder and drag your edited cerebrum mask to the “Mask” subfield in the image display toolbar. (To open the image display toolbar, click on the scan in BrainSuite and push “i” on the keyboard, or click on the icon, to the left of the mask icon, at the top of the window.) 2. At the top of the screen, select the coronal view (6 buttons to the right of the mask icon in BrainSuite 15). Typing + or – on your keyboard will allow you to zoom in or out on the image. 3. In the image display toolbar, there are three grayscale colorbars. The first will allow you to brighten the darker parts of the scan for better viewing. Select the triangle at the top of the colorbar and drag it downwards. 4. Scroll through the mask until you find the place where the cerebellum extends to its lowest point. Alt-click and drag the scan to align this point with the bottom of your window. You will need to enlarge the scan so that it can be moved around within the BrainSuite window. You can do this by pressing the + button on your keyboard. Your 201 screen should now look like this: 5. Scroll forward through the mask until you get to the forward part of the brainstem, just at the point where the brainstem appears. Click on the image and press “m” on the keyboard to open the mask-editing window, and check “edit mask”. Use control+right click to start tracing out the brainstem and include it in the mask (see orange arrow below). Continue scrolling backwards through the brain, including more of the brainstem: 202 6. Continue scrolling backwards through the brain. When the cerebellum and brainstem appear, be sure to include them in the mask, stopping where the image meets the bottom of the screen (which you aligned to the lowest part of the cerebellum in step 4). 203 7. Continue through the brain until all of the cerebellum is included in the mask. 8. Save the mask in your edits folder and close BrainSuite. Be very careful not to save it over your cerebrum mask. The correct name should be [sbjID].mask.nii.gz, without the word “cerebrum” in the filename. 204 Inner Cortical Mask (ICM) You should now have the cerebrum and full-brain masks saved in your “Edits” subfolder within your subject folder. If you’re working on a year 1 scan, you should also have a hand edited bfc file in your “Edits” folder. Generating an initial ICM Scan 1/Year 1 Method: 1. Transfer your hand-edited bfc file into a temporary folder to avoid accidently over- writing hand-edited files. Remove “.bfc” from the file name, and open the file in BrainSuite 2. Open the image display toolbar and drag the full-brain mask to the mask subfield. Scan 2/Year 3 Method: 1. Open the MPRAGE (e.g. “m7777_NP.nii.gz”) in BrainSuite from your main subject folder, and load the full-brain mask from your “Edits” folder. 2. From the “cortex” menu, open the cortical extraction sequence. Uncheck “Skull stripping” and “Skull and scalp”. Press “stage” 3 times to run the “Nonuniformity correction”, “Tissue classification”, and “Cerebrum labeling”. 205 3. After completion of the “Cerebrum labeling” step, retrieve the hand-edited cerebrum mask from your edits folder and load it into BrainSuite to replace the automatically generated one in the previous step. 4. Use the “stage >>” button to continue through the “Inner Cortical Mask”, “Scrub Mask”, “Topology Correction”, “Wisp removal” and “Inner cortical surface” stages. The mask you will edit should now be saved as “[sbjID].cortex.dewisp.mask.nii.gz” in your subject folder. Scan 3/Year 5 and Adult Tech Scans Method: Scan 3 differs from scan 2 only in step 4 above, and only in the “Inner cortical mask” stage. The “inner cortical mask” stage of the cortical extraction sequence has a parameter, the “Tissue threshold”, that was always left at the default value of 0.5 in scan 2. However, that requirement has now been relaxed. The “Tissue threshold” parameter defines the threshold of brightness a voxel has to be to be counted as white matter. Lowering the threshold means that the mask will include more white matter. Depending on the quality of the scan, the contrast between the gray and white matter may suffer, and this can lead to a stunted-looking ICM. (This is especially true for head motion cases.) Start with the tissue classification set at 0.5, and follow all steps for scan 2 as described. At the end of step 4, examine the inner cortical surface and mask to check the quality of the ICM. A good ICM should lead to well-defined, deep gyri and sulci. If the initial generation of the mask is poor, however, the gyri will look stunted. Lower the tissue threshold to 0.4 and repeat all steps 206 to generate a new mask. Repeat with different values of the tissue threshold (e.g. 0.35, 0.45, etc.) until the initial ICM is of suitable quality. Editing the ICM Editing the ICM is far more complex than the other masks, requiring you to monitor all three views (sagittal, coronal, and axial), and compare your progress to the generated surfaces. General Instructions on Editing the ICM 1. Open BrainSuite and load the MPRAGE and the automated ICM. Leave BrainSuite in the default view. Close the “BrainSuite Log” window at the bottom of the screen to give yourself more room to display the scan and surface. 2. Open the delineation toolbox (aka the mask toolbox) by clicking the mask icon in the top left, or by clicking on the scan and pressing the “m” key on your keyboard. 3. Click the “make surface” button to generate a surface from your mask in the surface view (bottom right). Press Ctrl-V (Cmd-V on a mac) to get rid of the black panels in the surface view and better view your surface. 4. From the mask toolbox, click “edit mask” and select a brush size. Edit the desired area of the mask, and then press “make surface” in the mask delineation toolbox. 5. Open the “surface display” toolbox by clicking on the MPRAGE and pressing “s” on the keyboard. A list of all surfaces you’ve created is at the bottom of the toolbox. The 207 newest surfaces show up at the bottom of the list. You will need to delete older surfaces to view only the newest surface you created, and thus see the effect of your edits on the mask. To delete a surface, click on the surface in the list and press the button with an “x” on it underneath the heading “Surface Properties” in the surface toolbox. 6. If editing the mask creates a hole in the surface, double click on the surface to move the cross-hairs to that point in the mask. Typing + or – on the keyboard will zoom out or in on the location of the crosshairs on the mask. Find the error in the tracing and correct it, checking your correction by creating a new surface. 7. When you have finished editing the cerebrum mask, save it in your edits folder with the name “[sbjID].cortex.dewisp.mask.nii.gz”. Correcting the area around the parahippocampal gyrus. Areas closer to the ventral side of the brain tend to be brighter, and the ICM tends to be very over inclusive around the parahippocampal gyrus. Using the default view in BrainSuite that shows all 4 views at once, begin working in the coronal panel: 208 Go the entire length of the PHG, tracing as in the example above. Then check your work in the sagittal view and against the surface: 209 210 Pial Extraction Sequence The pial extraction process requires 3 hand-edited masks: the cerebrum mask, the full-brain mask, and the inner cortex mask. The method for scan 1 is not the same as it is for the scans in later years, due to changes in processing introduced after the installation of the new scanner. The instructions below are valid as of version 15b, but are unchanged from earlier versions of BrainSuite. Method for Scans from Year 3 and Later 1. Open the MPRAGE ([subject base].nii.gz) from the main subject folder, and load the full- brain mask from your edits folder. 2. From the Cortex menu, open the “Cortical Extraction Sequence”. In the window that pops up, uncheck “Skull stripping”, “Skull and scalp”, “Inner cortical mask”, “Scrub mask”, “Topology correction”, and “Register and label brain.” 3. Click “Stage >>” 3 times to run the “Nonuniformity correction”, “Tissue classification”, and “Cerebrum labeling.” This will in turn generate the bfc (bias field correction) file, the pvc label (tissue classification), and a raw cerebrum mask, along with some other files. 4. Copy your edited masks from your edits folder to your main subject folder. At the prompt, click “Copy and Replace” for all files. 211 5. Load the inner cortex mask and click “Stage >>” twice to run “Wisp removal” and “Inner cortical surface”. 6. You should now see the “Pial surface” submenu on the Cortical Surface Extraction window. Click “Load Custom Mask” and select your edited cerebrum mask. This will constrain the growth of the pial surface to the hand-edited boundary. 7. Click “Run All” to run the remaining two steps and complete the process. This will generate inner, mid cortex, and pial surfaces for each hemisphere, which are necessary input files for SVREG and surface correction steps. The “Pial surface” step will take about 15 minutes. 212 REGISTRATION SVREG SVREG must be run in a temporary folder on the linux machine. Attempting to run scripts directly on the server from the linux machine usually fails due to broken connections with the server. 1. Copy the subject folder into a temporary folder on the linux machine. 2. Identify the appropriate atlas and copy it from the server to the following location on the linux machine: Desktop à BrainSuite à BrainSuite15b à svreg. You must use this location, as BrainSuite’s scripts will run into errors if the atlas is located anywhere else. 3. Open SVREG_Scan3.sh, located on the linux desktop, by right-clicking it and selecting “open with text editor”. [If for some reason this file has been deleted, open the text editor and create a new file with this name.] 4. Here is a sample SVREG command, like you will see in that file: sh /home/dniuser/Desktop/BrainSuite/BrainSuite15b/svreg/bin/svreg.sh /home/dniuser/Desktop/SCAN3_SVREG/Detailed_SMA/m9097AD_GG/m9097AD_GG /home/dniuser/Desktop/BrainSuite/BrainSuite15b/svreg/m6372AD_GG_atlas_detSMA/ m6372AD_GG_ave As you can see, it consists of four parts, the last two of which you must edit: 213 a. An initial ‘sh’ that tells the linux machine it’s a shell script. This does not need to be changed. b. The path to the svreg script: /home/dniuser/Desktop/BrainSuite/BrainSuite15b/svreg/bin/svreg.sh This, too, does not need to be changed. c. The subject on which you’re doing SVREG. This must consist of BOTH the subject folder and the base name of the subject. The base name of the subject is the beginning part of every filename in the subject folder. In the above example, the subject folder is everything through “…m9097AD_GG/” and the subject base is “m9097AD_GG”. d. The atlas you’re using to register the subject. Like in part ‘c’, this must contain both the folder name of the atlas, and the base name of the atlas. 5. When you have finished editing the command, save the .sh file. Open a terminal and navigate to the Desktop, where the .sh file is located. 6. On the command line, type ‘sh SVREG_Scan3.sh’. Press enter. The script takes about 2 hours per subject. 7. Contact Anand if anything goes wrong.
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Heydari, Panthea
(author)
Core Title
Engagement of the action observation network through functional magnetic resonance imaging with implications for stroke rehabilitation
School
College of Letters, Arts and Sciences
Degree
Doctor of Philosophy
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Neuroscience
Publication Date
07/20/2017
Defense Date
05/04/2017
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University of Southern California
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action observation network,fMRI,functional neuroimaging,mirror neuron system,OAI-PMH Harvest,stroke
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English
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Winstein, Carolee (
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), Aziz-Zadeh, Lisa (
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panthea.heydari@gmail.com,pheydari@usc.edu
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https://doi.org/10.25549/usctheses-c40-406229
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Tags
action observation network
fMRI
functional neuroimaging
mirror neuron system
stroke