Julius P. A. Dewald, PT, Ph.D. - US grants

DESCRIPTION (provided by applicant): Movement discoordination following stroke is caused by the emergence of stereotypic multi-joint movement patterns (synergies), reflecting a loss of independent joint control, and hyperactivity of spinal reflexes, including the stretch reflex (spasticity). Specifically in the paretic upper limb, shoulder abduction/elbow flexion (flexor-synergy) and shoulder adduction/elbow extension (extensor-synergy) are coupled in moderately to severely impaired stroke survivors. As part of the first cycle of this R01 proposal, we quantified these coupling patterns isometrically by using a 6 Degree of Freedom (DOF) load cell. Furthermore, we discovered that subjects are constrained to these abnormal coupling patterns. The general aim of this R01 renewal is to extend the research of discoordination following stroke to arm movement and to elucidate the relative effect of abnormal synergies and spasticity on the 3-D workspace of the paretic limb using 3D robotics. More specifically we intend to: 1) identify and quantify, under dynamic conditions, the effect of gravity on 3-D upper extremity workspace in general and, more specifically, on active elbow/shoulder range of motion;2) determine the relationship between abnormal shoulder/elbow torque patterns and hyperexcitable stretch reflexes during 3-D multi-joint ballistic reaching movements;3) estimate the possible contribution of bulbospinal systems in the expression of abnormal torque patterns and hyperexcitable stretch reflexes using asymmetric tonic neck reflexes (ATNRs) and transcranial magnetic stimulation (TMS) in chronic hemiparetic stroke subjects. We predict that the workspace of the paretic arm will decrease for increasing levels of abduction torques and shoulder abduction angles. This will be studied by changing the level of the subject's arm support and movement direction over horizontal versus inclined and declined planes generated by a 3-D force controlled robot arm. Furthermore, we predict and will provide preliminary evidence that stretch reflex excitability, tested by robot generated stretches at the onset of reaching movements, will increase for increasing level of active limb support. However, since reaching movement will also slow down, we will determine if and when spasticity plays a role in the workspace of the paretic limb. Finally, we predict that the ATNR has a profound effect on the paretic limb's workspace. This expected finding, combined with increased latencies of TMS induced motor evoked potentials (MEPs) and ATNR induced changes in MEP magnitudes in the impaired arm, points to an increased reliance on bulbospinal systems as an important source for discoordination following stroke. Determining the mechanisms underlying upper extremity movement disorders following hemiparetic stroke by using 3D robotics is likely to result in the design of novel therapeutic interventions. These interventions will incorporate 3D robotics-mediated virtual mechanical and visual environments to improve arm function.

This is the first year funding of a three-year continuing award. This project addresses the need to assist humans in heavy materials handling, since such tasks expose the worker to known risk factors for work-related musculoskeletal disorders, such as lifting, bending, twisting, and maintenance of awkward postures. This project will study the use of cobots to implement ergonomic guiding surfaces to assist a human in the manipulation of a heavy load. With such a mechanism, the load can be constrained to move along a frictionless guide, and the human is allowed to apply forces in directions which are comfortable while the guide directs the motion to the goal. Cobots use rolling contacts to directly implement passive guiding constraints, and as a result they are safer to interact with and use less power than a conventional robot. To design assistive guide constraints, the project will study how humans naturally interact with constraints assuming that the essential nature of this interaction can be modeled by the human's desire to minimize some notion of effort. With this model, The PIs will design guides that minimize the necessary human effort and will experimentally verify the correctness of the model. The PIs will develop software for automatically planning near-optimal guides in cluttered workspaces and will test the guides using cobot hardware on realistic materials handling tasks. The resulted ergonomic virtual surfaces in materials handling will reduce the occurrence of work-related musculoskeletal disorders. It will also increase productivity, providing an intuitive and safe interface between human and computer. Finally, this work will expose new principles in human motor control, as the design of assistive guiding surfaces requires a better understanding of how humans interact with constraints.

DESCRIPTION (provided by applicant): The objective of this R03 application is to demonstrate quantifiable spatiotemporal differences in macroscopic electrical activity of human sensorimotor cortices during voluntary isometric torque generation in the upper limb. Using a combination of high-resolution EEG measures, a novel quantification technique and a 6 degree of freedom load cell controlled isometric paradigm, it is proposed to quantify differences in spatiotemporal electrical brain activity during the generation of static torques in different directions and of different magnitudes. Specifically, it is postulated that the magnitude (intensity) of electrical brain activity scales monotonically as a function of load magnitude (Aim 1). Furthermore, it is postulated that the spatial organization of cortical activity, expressed in terms of an area of activation and its center, is a function of load direction and not a function of load magnitude (Aim 2). Cortical locations identified by the EEG measures will be verified using event-related fMRI (Aim 3). The preliminary results indicate the presence of a clear monotonic relationship between the magnitude of cortical activity and the magnitude of joint torque generation (Aim 1). Preliminary findings also demonstrate a strong spatiotemporal correlation between the location of centers of electrical brain activity and elbow/shoulder static joint torque direction (Aim 2). Specifically, pilot data demonstrates that the approach has the ability to separate joint torque direction at a single joint. For example, one is able to distinguish, for the first time, quantifiable differences between the location of cortical activity associated with elbow flexion and elbow extension as well as shoulder abduction and shoulder adduction torques. This investigation will expand the study of cortical activity as a function of joint torque direction by increasing the number of torque directions generated at the elbow and shoulder joints from four to eight directions. The characterization of spatiotemporal electrical brain activity proposed in this study is likely to lead to future research on cortical organization which will seek to distinguish joint torque from muscle activation based encoding schemes. Furthermore, quantification of spatiotemporal electrical brain activity in healthy human subjects provides the backdrop for similar studies in stroke subjects, which will examine the cortical substrates underlying the known impairments of available muscle and torque combinations in this population. Taken as a whole, the proposed study may substantially enhance our understanding of motor cortical activity in the healthy human brain and provide foundations for further scientific inquiry into mechanisms of cortical reorganization following hemiparetic stroke, which may lead to the development of more effective neuro-therapeutic interventions.

DESCRIPTION (provided by applicant): Loss of independent control of joint movement in the impaired limb is a cardinal sign of stroke that is expressed in the form of stereotypic multi-joint movement patterns. Work from our laboratory has produced evidence for a loss of certain muscle coactivation patterns and associated abnormal shoulder/elbow torque coupling in the paretic arm of individuals with hemiparetic stroke. The general aim of this proposal is to elucidate the role of sensorimotor cortices in the loss of independent joint control of the paretic upper limb following stroke. We propose to study 20 individuals with chronic stroke and 20 control subjects to identify and quantify the characteristics of sensorimotor cortical activity related to the generation of isometric shoulder abduction/adduction and elbow flexion/extension torques. We hypothesize that an increased overlap of sensorimotor cortical activity is present in individuals with stroke (Aim 1). This aim will be realized using a 6 degree of freedom (DOF) load cell to provide simultaneous measurements of elbow and shoulder torques while measuring EEC from 163 scalp sites and EMG from 10 muscles in each arm. We postulate and have provided preliminary evidence for a significant overlap between cortical activity related to shoulder abduction and elbow flexion torque generation in chronic stroke subjects while not in able-bodied subjects. Subsequently, we plan to elucidate the relationship between the overlap of cortical activity and abnormal shoulder/elbow torque coupling in the paretic arm (Aim 2). We postulate that an increase in the overlap of cortical current activity is a reason for the abnormal torque coupling and serves as a predictor of the severity of discoordination in individuals with stroke. Finally, we propose to investigate the effect of a novel multidegree of freedom isometric training protocol on the overlap of cortical activity in individuals with stroke (Aim 3). Results from our recent work, using this training protocol, have shown a reduction in abnormal torque coupling between shoulder and elbow following an eight week intervention in all stroke subjects (n=7). We postulate and have provided preliminary evidence for a reduction in cortical-activity overlap in concurrence with a training-induced reduction in abnormal torque coupling. In conclusion, the combination of multichannel EEG imaging with a well controlled isometric elbow/shoulder torque generating task in subjects with chronic hemiparetic stroke is unmatched in the current literature. This study will provide new indices in the evaluation and study of discoordination as well as dynamic information on cortical plasticity in individuals with chronic hemiparetic stroke undergoing an upper extremity physical intervention. As such, the proposed study will substantially enhance our understanding of mechanisms driving discoordination in hemiparetic stroke and will provide foundations for further scientific inquiry into the development of more effective therapeutic interventions.

[unreadable] DESCRIPTION (provided by applicant): Movement discoordination following stroke is caused by the emergence of stereotypic multi-joint movement patterns, reflecting a loss of independent joint control, and hyperactivity of spinal reflexes including the stretch reflex (spasticity) and the flexion withdrawal reflex. The commonality between the emergence of abnormal synergies and spinal reflex hyperexcitability following stroke is postulated to arise from an increased bulbospinal monoaminergic drive to the spinal cord following a loss of corticospinal and corticobulbar projections. Evidence for increased bulbospinal input include increased motoneuron excitability, depressed short latency and enhanced long latency flexion reflexes, and a diminished capacity for selective movement due to the emergence of stereotypic synergic movement patterns. We propose to examine the effect of an increased bulbospinal monoaminergic drive on the expression of abnormal movement patterns and spinal reflexes following stroke by manipulating the neural excitability at the spinal cord and/or brainstem using either Tizanidine (TIZ) or Tamsulosin (TAM). It is our intention to: 1) identify and quantify the presence of increased noradrenergic input to the spinal cord following a stroke; 2) elucidate mechanisms underlying hyperactive flexion and stretch reflexes following stroke; 3) investigate the role of monoaminergic pathways in the expression of abnormal muscle and torque synergies under isometric and dynamic conditions in the paretic upper limb following stroke. We predict that inhibition of brainstem monoaminergic pathways as well as group II and high threshold afferents at the cord, through administration of a noradrenergic (NE) a-2 agonist (TIZ), will result in the reduction of discoordination, flexion reflexes and spasticity in individuals with stroke. We also predict that reduction of NE mediated excitation of motoneurons, through the administration of a selective NE a-1 antagonist (TAM), will result in the reduction of volitional strength, spasticity, and magnitude of the flexion reflex. Upper extremity discoordination is expected to remain unaltered by the administration of TAM because of its lack of supraspinal effects. The knowledge generated by this study seeks to reveal the primary mechanisms underlying the presence of discoordination and hyperactive spinal reflexes following stroke. The identification of these mechanisms may direct the development of novel pharmacological agents that target bulbospinal mechanisms underpinning upper extremity discoordination [unreadable] [unreadable]

PROJECT SUMMARY Pediatric-onset hemiplegia (PH) causes movement impairments on one side of the body and accounts for more than a third of all cases of cerebral palsy, the most common motor disability in childhood. Motor impairments in this population include weakness, movement synergies, and coupling movements between limbs (between arms and between paretic arm and legs), all of which limit independence with functional mobility throughout the lifespan. Crucial tasks, such as reaching and grasping, required for countless daily activities including participating in the classroom, become limited or impossible. In the previous cycle of this R01, we discovered that the timing of brain injury during neurodevelopment impacted the expression of weakness, involuntary coupling of shoulder abduction with elbow, wrist, and finger flexion (flexion synergy), and involuntary coupling between upper limbs during isometric tasks. Our previous work uncovered the importance of the timing of the injury on the preservation of neural structures, expressed in the integrity of white matter, as they may be affected differently based on the stage of neurodevelopment when the injury occurs. During early injuries (PRE-natal), there may be preservation of direct ipsilateral corticospinal projections that are present as part of typical neural development. We hypothesize that this explains the reduced presence of the flexion synergy and the greater movement coupling between upper limbs. Conversely, in later injuries (PERI- and POST-natal) we hypothesize that the developmental pruning of these ipsilateral corticospinal projections is in process (PERI-natal) or has already occurred (POST-natal) leading to increased reliance in indirect ipsilateral corticoreticulospinal pathways to control movement of the paretic limbs. These indirect pathways branch significantly at the spinal cord, explaining the presence of the flexion synergy and abnormal involuntary coupling between the paretic leg and arm. In an effort to determine the effects of time of injury and limb loading on motor impairments during functional reaching-grasping tasks in PH and the link to neural microstructural morphology, we propose to: 1) quantify upper extremity reaching distance and hand opening/closing ability; 2) determine the expression of between-limb movement coupling; and 3) identify the changes in white and gray matter complexity of motor pathways in ipsilesional and contralesional hemispheres as well as the brainstem. As such, the proposed research will, for the first time, investigate the effect of time of brain injury on motor pathway complexity in individuals with pediatric-onset hemiplegic who express within-limb and between-limb coupling dysfunction. This will provide the foundation for the development of more effective targeted, time-of-injury specific interventions for the treatment of abnormal within- and between-limb coupling to improve functional capabilities in this population.

The goal of this training program is to seek continued support of the Interdisciplinary Graduate Education in Movement and Rehabilitation Sciences (IGE-MRS) program, created at Northwestern University between the departments of Biomedical and Mechanical Engineering and the department of Physical Therapy and Human Movement Sciences. The mission of the IGE-MRS program is to expose engineering students to a graduate education that combines engineering, neurobiology and physical therapy and human movement sciences coursework along with the associated research experiences through a DPT (Doctor in Physical Therapy) - PhD (Engineering) dual degree. The IGE-MRS program is the first program of its kind in the US to combine solid training in fundamental neurobiology and clinical physical therapy with a solid education in engineering. This interdisciplinary training allows for the development of the scientific basis required for understanding the pathophysiological mechanisms underlying movement disorders and for designing effective rehabilitation interventions and devices. The program mentors have successful science careers as engineers, neuroscientists and clinicians, and represent a broad range of expertise relevant to movement and rehabilitation science and physical therapy. Northwestern University has a long and recognized history in the study of motor control, motor disability and recovery, and neural reorganization. Extensive research is performed in these areas at various levels, from basic animal and human studies focused on the control of movement and movement disorders, to the development of novel rehabilitation interventions and devices that address these movement disorders. Areas of research represented in participating labs fall loosely into three main areas: neurobiology of movement behavior and disorders, rehabilitation device and interface development, and musculoskeletal pathophysiology and modeling. The breadth and depth of movement and rehabilitation research at Northwestern provides a robust translational environment for our IGE-MRS trainees. In this renewal application, we seek to continue to build our program based on past experience and increase our impact through enhancements designed to recruit and enroll a more diverse trainee pool, expand representation of a greater number of laboratories and research areas especially in Mechanical Engineering, and strengthen the career development opportunities that facilitate the transition from clinical to research training and beyond into independent clinician scientists. Through these innovations and the continuation of successful practices already in place, we fully expect to continue advancing the science and practice of movement and rehabilitation science by training the next generation of DPT-PhDs in Engineering. We intend to support a total of 6 DPT-PhD students per year and up to one affiliate trainee per year during this competitive renewal. The T32 grant will provide support for a total of two years per trainee during their PhD training. Northwestern will support the first year of PhD training, supplement tuition and stipend during the two years of NIH support, and then fully support the entirety of the DPT training of this unique training program.

DESCRIPTION (provided by applicant): The goal of this proposal is to attain support for a new interdisciplinary program in Movement and Rehabilitation Sciences (MRS), created at Northwestern University under the umbrella of the Northwestern University Interdepartmental Neuroscience (NUIN) program. The mission of the NUIN-MRS program is to train students with clinical and life/applied science backgrounds to become rehabilitation scientists in basic, translational or clinical research. These rehabilitation scientists will have the ability to integrate knowledge from the various disciplines involved in MRS, including neuroscience and physiology, engineering and clinical sciences. The training program will focus on the neurobiology of movement and rehabilitation sciences, with three main goals: 1) understanding the neurobiology of movement behavior and disorders, 2) identifying and addressing the need for quantitative methods in MRS, and 3) applying this knowledge to the development of effective rehabilitation interventions. Northwestern University has a long and recognized history in the study of motor control, motor disability and recovery, and neural reorganization. Extensive research is performed in these areas at various levels, from basic animal and human studies focused on the control of movement and movement disorders to the development of novel rehabilitation interventions that address these movement disorders. The interdisciplinary nature of the program will allow close interaction between clinical investigators and basic and applied sciences investigators, providing a unique opportunity for training in translational research, going from the laboratory to the clinic. The PIs intend to support a total of 4 predoctoral students in year 1 of the training program and 7 trainees in each of years 2-5. The program will provide support for a total of two years for each trainee. PUBLIC HEALTH RELEVANCE: The number of individuals with disabilities and the extent of the disabilities continue to increase with a clear impact on the need for developing better and more effective rehabilitation interventions. The proposed NUIN-MRS PhD program will train rehabilitation scientists based on solid fundamental science principles combined with quantitative methods to allow them to establish research programs to develop effective rehabilitation interventions and, more importantly, transfer them to the clinic.

DESCRIPTION (provided by applicant): The goal of this proposal is to attain support for a new Interdisciplinary Engineering Career Development Center in Movement and Rehabilitation Sciences created by a consortium of leading institutions in the field including Northwestern University, the Rehabilitation Institute of Chicago, University of California Irvine, University of North Carolina, Case Western Reserve University, Marquette University, Stanford University, and University of Delaware. The mission of the proposed program is to develop scholars with engineering and other quantitative backgrounds to become successful rehabilitation scientists in basic, translational and/or clinical research. This would be the only program of its kind to focus on engineering-trained investigators. The PIs believe that these individuals, who already possess strong quantitative, problem-solving, programming, signal analysis and mechatronics skills, are uniquely positioned to make a significant impact on the field of quantitative movement and rehabilitation sciences (MRS) and its translation to rehabilitative care. The proposed career development program seeks to provide scholars with: 1) In-depth understanding of rehabilitation patient-centered clinical problems; 2) Career development opportunities and mentoring to broaden their MRS research and training; and 3) Mentoring in translational research to increase the impact of their work. The PIs will accomplish these goals by using a dual mentorship model with a senior engineering faculty member and a senior clinical rehabilitation faculty member. In addition, scholars will participate in sabbatical experiences where they can further their knowledge and research skills in rehabilitation and engineering laboratories. The participating institutions have a long and recognized history in the study of the neurobiology of movement behavior and dysfunction, rehabilitation robotics, sensory-motor neural machine interfaces, and musculoskeletal modeling and dysfunction. Extensive research is being performed in these areas, across the continuum, from basic animal and human studies focused on the control of movement and movement disorders, to the development of novel rehabilitation robotics interventions that address these movement disorders. This impressive array of established research programs will not only provide a fertile ground for the development of engineering scholars in the field of MRS, but will also foster the creation of new interdisciplinary and inter-institutional collaborations that will bring new discoveries to fruition. The PIs intend to supporta total of 4 scholars in year 1 of the career development program, and 8 scholars in subsequent years. The program will provide support for a total of two years for each scholar.

? DESCRIPTION (provided by applicant): Impaired arm function is a major cause of chronic disability among stroke survivors. A number of treatment approaches have been developed to facilitate the recovery of arm function, targeting stroke induced motor impairments such as paresis, spasticity and losses of independent joint control that result in involuntary elbow, wrist and finger flexion while lifting the arm (i.e., the flexion synergy). However, our understanding of how muscle adapts to these impairments over time is not clear at this juncture nor how changes in muscle properties impact the functional use of the paretic arm. Therefore, we propose to determine the extent of structural changes in the skeletal muscles of the paretic arm due to the persistence of a prominent flexion synergy, paresis, and the associated disuse of the paretic upper limb. Subsequently, we propose to demonstrate the effects of these secondary musculoskeletal changes on the ability to generate functional arm movements by using novel simulations of combined arm and hand motion. We postulate that the flexion synergy, paresis, and the chronic disuse of the paretic upper limb that results from the stroke, induce substantial changes in both passive and active muscle properties, thus limiting the ability to generate functional arm movements, even if normal neural drive from the brain would be restored. In Aim 1, we propose to investigate the relationship between the abnormal flexion synergy and increases in passive stiffness that result in more flexed arm postures in individuals with stroke. In Aim 2 we propose to characterize changes in muscle architectural parameters (i.e., fascicle and sarcomere length, and muscle volume) following stroke and determine the effect of any structural deviations from age-matched able-bodied individuals on maximum isometric force generation ability, as indicated by calculating muscle physiological cross-sectional area, a standard anatomical measure of an individual muscle's ability to generate force. Finally, as part of Aim 3 we propose to employ state-of-the-art forward dynamics simulation techniques using an upper limb model that integrates the arm and hand to determine the extent to which altered muscle properties (Aims 1 & 2) and abnormal muscle co-activation patterns (Aim 1) account for the severe limitations in functional use of the upper limb experienced by individuals with chronic hemiparetic stroke. The rationale that underlies the proposed research is that determining the exact role of altered muscle properties on functional use of the paretic upper limb following chronic hemiparetic stroke will allow for the design of more effective rehabilitation interventions This will change the way clinicians approach the rehabilitation of the paretic upper limb by highlighting the relative importance of the various musculoskeletal changes which combined with the proposed measurement tools provide the means to design and test therapies to reduce or prevent detrimental changes in muscle following stroke.

Project Summary: The goal of this competitive renewal proposal is to continue the highly successful Interdisciplinary Engineering Career Development Center in Movement and Rehabilitation Sciences created by a consortium of leading institutions in the field, including Northwestern University, the Rehabilitation Institute of Chicago, University of California Irvine, Medical University of South Carolina/Clemson University, University of North Carolina/North Carolina State University, Case Western Reserve University, Marquette University, Stanford University, and University of Delaware. The mission of our program is to develop top scholars with engineering and other quantitative backgrounds to become successful rehabilitation scientists in translational research. This is the only program of its kind to focus on engineering-trained investigators. We believe that these individuals, who already possess strong quantitative, problem-solving, programming, signal analysis and mechatronics skills, are uniquely positioned to make a significant impact on the field of quantitative movement and rehabilitation sciences (MRS) and its translation to rehabilitative care. The proposed career development program will provide scholars with: 1) In-depth understanding of rehabilitation patient-centered clinical problems; 2) Career development opportunities and mentoring to broaden their MRS research and training; 3) Mentoring in translational research; 4) Technology transfer and translation training to increase the impact of their work. We will accomplish these goals by using a dual-mentorship model with both a senior engineering faculty member and a senior clinical rehabilitation faculty member assigned to each scholar. Moreover, new this cycle, scholars will participate in a clinical bootcamp followed by a mentored clinical experience that will allow them to integrate their newly gained knowledge of pathophysiology to clinical manifestations of movement disorders. Also, scholars will benefit from increase exposure and networking through organized conference sessions. Finally, they will be participating in grant review groups made up of fellow scholars and a member of the executive committee. These experiences are designed to help our scholar?s identify significant clinical needs related to their domains of expertise as well as to become successful rehabilitation scientists. The participating institutions have a long and recognized history of rehabilitation research including studies on the neurobiology of movement behavior and dysfunction, rehabilitation robotics, neural machine interfaces for the restoration of sensorimotor function, and musculoskeletal modeling. Extensive research is being performed in these areas, across the continuum from fundamental animal and human studies to the development of novel rehabilitation paradigms. This impressive array of established research programs provides a fertile ground for developing our engineering scholars and fostering new interdisciplinary and inter-institutional collaborations to advance our field. We intend to support a total of four scholars in year one of the career development program, and six scholars in subsequent years. The program will provide support for two years for each scholar.

Abstract. Motor impairments post-stroke, such as the upper limb flexion synergy and abnormal stretch reflexes, greatly affect an individual?s ability to implement activities of daily living. Despite the development of various clinical interventions for motor recovery after stroke, rehabilitation treatments, especially in more impaired individuals, are only minimally effective. This is due to: 1) many remaining gaps in our understanding of specific mechanisms underlying motor impairments post stroke that inform clinical practice, and 2) lack of sensitive biomarkers to determine the neuroplasticity resulting from interruptions of neural pathways caused by the stroke and during recovery. Our long-term goal is to develop a sensitive way to quantitatively assess the lesion-induced utilization of remaining motor pathways post stroke, which would allow better examination of stroke recovery and evaluation of rehabilitation interventions. Our previous studies indicate that motor impairments post hemiparetic stroke are likely caused by an increased reliance on contralesional indirect motor pathways via the brainstem, following stroke-induced losses of ipsilesional corticospinal projections. Thus, the objective of this proposal is to quantitatively determine the usage of indirect motor pathways and its link to the expression of the flexion synergy and abnormal stretch reflexes, by examining changes in neural connectivity of motor pathways as a function of shoulder abduction (SABD) load. In contrast to the direct corticospinal tract, these indirect pathways contain more synapses, which thus may cause an enhanced nonlinear neural connectivity via the motor pathways due to the nonlinear sigmoid shape of synaptic behavior and its cumulative effect across synapses. Thus, our central hypotheses are that: 1) an increased usage of indirect motor pathways while lifting the paretic arm, requiring SABD and causing the flexion synergy, will lead to enhanced nonlinear connectivity between brain and muscle activity; 2) the recruitment of indirect motor pathways will also affect the stretch reflex, in particular, its transcortical reflex component, resulting in increased nonlinear connectivity between stretch perturbations and muscle activity. Finally, these indirect pathways may prolong the neural transmission delay in the transcortical reflex loop, resulting in an increased time lag between perturbations and muscle activity. Using our recently developed nonlinear connectivity method and mechanically well-controlled experimental paradigms, we aim to test these hypotheses by: 1) comparing linear vs. nonlinear connectivity between brain and muscle activity during the generation of different levels of SABD torque in individuals post hemiparetic stroke; 2) quantifying changes of nonlinear connectivity and time delay of the stretch reflex post-stroke as a function of SABD torque level. As such, this project will provide new sensitive biomarkers that determine the recruitment of indirect motor pathways resulting in functional disability of upper extremity post hemiparetic stroke. This will also lead to a better understanding of neural mechanisms underlying stroke-induced motor impairments that inform clinical practice to combat the flexion synergy and associated hyperactive stretch reflexes following a unilateral brain injury.

Project Summary Impaired arm and hand function is a major cause of chronic disability among stroke survivors. In addition to weakness or paralysis, the arm/hand is also affected by the abnormal flexion synergy ? involuntary elbow, wrist, and finger flexion when an individual attempts to lift the arm. The flexion synergy compromises the ability to reach and open the hand and reduces the control of grasp strength during functional tasks, thus compounding the stroke survivor?s functional deficits. Most current treatments in mild to moderately impaired individuals focus on reversing weakness at the elbow/hand without regard to proximal joints which can have a detrimental effect on reaching and grasping based on the progressive expression of the flexion synergy. The fine motor control required for normal arm/hand function is largely driven by the contralateral corticospinal tract. After corticospinal and corticobulbar (i.e., corticofugal) pathways are damaged by a stroke, there is increased reliance on contralesional cortico-bulbo-spinal tracts. Based on primate research, an increased reliance on these ?lower-resolution? systems causes joint coupling patterns consistent with the flexion synergy pattern seen in humans post-stroke. Greater reliance on contralesional motor cortices over time is also expected to result in progressive increases in structural tract integrity in the contralesional- while reducing corticofugal tract integrity in the lesioned- hemisphere. Our central hypothesis therefore is that ischemic damage to the corticofugal tracts causes a greater reliance on contralesional indirect corticobulbospinal tract resulting in increased functional connectivity between contralesional cortex and brainstem nuclei and enhanced structural morphology of bulbospinal projections that are predictive of the expression of the flexion synergy and recovery of reaching and hand function. To test this hypothesis, we propose to quantify whether there is greater use of contralesional sensorimotor cortices as a function of abduction loading and motor impairment severity and its impact on reaching and grasping (Aim 1). We then propose to quantify the structural morphology and functional connectivity of corticospinal and contralesional corticobulbospinal projections to motor nuclei in the brain stem in chronic stroke participants (Aim 2). Lastly, we plan to conduct a longitudinal analysis of the relationship between structural morphology of contralesional bulbospinal projections and motor recovery, and specifically, evaluate early morphological change as a predictive biomarker for chronic motor recovery outcome (Aim 3). This is the first-time longitudinal change in brain function and structure will be linked to synergy induced motor impairments in the paretic upper limb of individuals with stroke. These structural and functional biomarkers of motor pathways changes will guide the timely application of anti-synergy interventions that will promote the maximal utilization of spared corticofugal resources in the lesioned hemisphere thus largely avoiding structural and functional changes to indirect contralesional motor pathways and minimizing the devastating effects of the flexion synergy.