Robert Louis Sainburg - US grants

DESCRIPTION: (Verbatim from application) Handedness, the manual asymmetry characterized by the tendency to favor one hand for performance of skilled unimanual tasks, is a prominent feature of human motor performance that is believed to result from differences in the neural control of each limb. However, the precise mechanisms responsible for handedness remain controversial. The proposed studies build on our current findings, which indicate interlimb disparities in the control of intersegmental dynamics. Previous research indicates that reaching movements are initially planned in terms of task relevant variables, such as hand movement direction and amplitude (Krakauer and Ghez, 1999), and that this plan must be transformed into muscle activations in order for movement to take place. This transformation relies on internal representations of musculoskeletal and task specific dynamics (Gandolfo, et at, 1996; Goodbody and Wolpert, 1998; Jordan and Rumelhart, 1992; Lackner and Dizio, 1994; Sainburg, et al, 1999; Shadmehr and Mussa-Ivaldi, 1994). We hypothesize that the dominant arm controller is specialized for developing and updating such neural representations. To test this hypothesis, we employ a unique experimental paradigm that we previously developed to investigate learning of novel intersegmental dynamics with the dominant arm (Sainburg et al., 1999). We will analyze movement strategies following adaptation to altered inertial dynamics, imposed by attaching a mass to an outrigger, either medial or lateral to the forearm. Because this manipulation specifically alters the amplitude of interaction torques acting between the segments, we can investigate the extent to which the Central Nervous System (CNS) represents these dynamics and, in turn, utilizes such representations for planning and executing subsequent movements. We will compare interlimb differences in adaptation to novel visual-motor transformations and to novel inertial dynamics, to determine the level of the motor control process at which handedness is expressed. We will investigate differences in both anticipatory mechanisms, as well as, visual and somatosensory based error correction mechanisms. By specifically manipulating the characteristics of movement targets, we will determine whether transfer of learning is greater for movements in which either interaction torques or net torques remain constant. We will then examine interlimb differences in the extent to which learning transfers across changes in the relevant torque. These studies will provide a more thorough understanding of the neural mechanisms underlying handedness, which is critical for clinical rehabilitation applications that address motor learning in patients with unilateral movement deficits.

DESCRIPTION (provided by applicant): Handedness is a prominent manifestation of asymmetry in neural organization that has previously been relegated as either an artifact of lateralization in non-motor systems, or as the simple effect of practiced patterns of hand use. The studies in the initial phase of this award gave rise to a new hypothesis, that handedness reflects a functional optimization process through which control of limb position and trajectory have become specialized. This theory diverges from other biological descriptions of motor lateralization in defining the control mechanisms that underlie handedness, and in proposing advantages for the non- dominant system. However, it remains speculative due to limited evidence for specialization of the non- dominant system. Our first aim tests whether the non-dominant system displays advantages in controlling limb position and posture, and explores the mechanisms that might underlie such advantages. The proposition that lateralization reflects an optimization process leads to two predictions about subjects with varied handedness: First, left handers should show specializations that mirror image those of right handers, and second, mixed handers should exhibit relative deficiencies in motor performance because they have not developed lateral specializations. These predictions are examined in our second and third aims, which serve as critical tests of our model. Our fourth aim examines the implications of changes in lateralization that might occur with aging. It has been well established that lateralization in certain cognitive functions decreases with age. We hypothesize that age-dependent reductions in motor lateralization might give rise to coordination deficits in elderly individuals, a phenomenon that remains incompletely understood. To test this idea, we will examine motor lateralization in three age groups that characterize the adult lifespan. The proposed research has strong implications for neural lateralization theory, as well as for human health. The idea that lateralization reflects specialization of each hemisphere for different functions might explain the role of ipsilateral hemisphere in controlling unilateral arm movements, an effect that is well documented but is not well understood. More importantly, unilateral hemisphere damage due to stroke produces ipsilesional deficits that limit functional performance and that have been shown to reflect motor lateralization. The proposed work should help elucidate the mechanisms that underlie such deficits.

DESCRIPTION (provided by applicant): Unilateral sensory-motor stroke can cause significant motor deficits in the arm and leg on the same side of the body as the lesion (ipsilesional), in addition to producing more severe deficits on the opposite side of the body (contralesional). While ipsilesional deficits have been recognized in the clinic for decades, therapeutic attention has understandably focused on the more severe nature of contralesional deficits. However, ipsilesional deficits have recently been shown to substantially limit efficient performance of functional tasks, including activities of daily living. Such limitations are not difficult to understand given that the ipsilesional arm tends to be used as the primary manipulator during both unimanual and bimanual tasks for patients with moderate to severe hemiparesis. These coordination deficits are thought to result from diminished contributions from the damaged hemisphere to control of the arm on the same side of the body, an idea supported by our preliminary studies. Based on the dynamic dominance model of motor lateralization, we hope to explain and predict the differential deficits in unimanual and bimanual coordination that result from either right or left hemisphere damage. The proposed studies exploit the expertise of two laboratories that have invested substantial effort in studying motor lateralization (Sainburg), and ipsilesional motor performance in stroke patients (Haaland). [We expect our results to have tangible applications to rehabilitation, including the development of interventions to improve ipsilesional and bilateral function in chronic stroke patients.] Our proposed experiments examine targeted reaching movements, using a custom designed virtual-reality system that allows real-time display and recording of bilateral arm movements. The first two aims directly examine predictions from our model of lateralization for ipsilesional motor control and learning. Specifically, we will examine whether intersegmental coordination deficits result from left hemisphere damage, while positional deficits result from right hemisphere damage. In addition, we will examine the potential effect of such coordination deficits on functional performance. Our second aim examines whether unilateral stroke produces motor learning deficits that vary with the side of the lesion. Our third and fourth aims address the specific control processes that might underlie ipsilesional deficits: First, we ask whether left hemisphere related deficits in coordination and adaptation are related to errors in predicting task dynamics. Second, we examine whether position errors that result from right hemisphere damage are accounted for by deficient impedance control mechanisms, or rather by deficits in specification of spatial locations. In our final study, we will test our model's predictions for bilateral coordination during virtual object transportation and manipulation tasks. This is particular important for patients with moderate to severe hemiparesis, who often rely on bimanual arm use to carry out activities of daily living. In addition, recent research has indicated that bilateral exercise can serve as an effective therapeutic modality for such patients (Harris-Love et al, 2005). ! PUBLIC HEALTH RELEVANCE: The American Heart Association reports that each year, about 780,000 people in the United States experience a new or recurrent stroke, a large proportion of which involves asymmetrical damage to the cerebral hemispheres. Because the cerebral hemispheres are not functional mirror images of one another, lesion to either hemisphere can produce unique deficits in both arms of stroke patients, including the non-paretic arm. The studies proposed here should lead to a more complete understanding of motor deficits in the non-paretic arm of stroke patients, and the effects of these deficits on both unimanual and bimanual coordination. This is particularly important for patients with moderate to severe hemiparesis, who tend to rely on the non-paretic arm to carry out activities of daily living. We expect that our findings should produce tangible applications to clinical rehabilitation, and to rehabilitation research.

Project Summary: In the previous cycle of this grant, we characterized hemisphere-specific motor control deficits in the non- paretic arm of unilaterally lesioned stroke survivors. Our preliminary data indicate these deficits are substantial and functionally limiting in patients with severe paresis. We have specifically designed an intervention to remediate the hemisphere-specific deficits in the non-paretic arm, using a virtual-reality platform, and then follow this training with manipulation training of a variety of real objects, designed to facilitate generalization and transfer to functional behaviors encountered in the natural environment. We propose a 2-site, two-group randomized intervention with a treatment group, which will receive unilateral training of the non-paretic arm, through our Virtual Reality and Manipulation Training (VRMT) protocol. This intervention protocol is grounded in the premise that targeted remediation of fundamental control deficits exhibited by the non-paretic arm will generalize and transfer beyond practiced tasks to performance of activities of daily living (ADL). This approach contrasts with the more pragmatic approach of task-specific training of essential ADL?s, which is limited in scope, more cumbersome, and ignores known fundamental motor control deficits. Our control group will receive conventional intervention, guided by recently released practice guidelines for upper limb intervention in adult stroke. The impact of the proposed research is that we address persistent functional performance deficits in chronic stroke patients with severe paresis, who?s non- paretic arm impairments are generally ignored in most current rehabilitation protocols. Our first aim addresses the overall effectiveness of this intervention, relative to our control group: To determine whether non-paretic arm VRMT in chronic stroke survivors with severe paresis will produce durable improvements in non-paretic arm motor performance that will generalize to improve functional activities and functional independence to a greater extent than conventional therapy focused on the paretic arm. Our second aim focuses on the mechanistic basis of potential training-related improvements in motor performance: To determine whether intervention-induced improvements in non-paretic arm performance are associated with improvements in hemisphere-specific reaching kinematics. Finally, our third aim monitors for potential negative effects of our experimental intervention on paretic arm impairment. We have already integrated the PI?s laboratories (Sainburg-PSU, Winstein-USC) for our pilot research project that has provided excellent support for aims 1 and 3. !