A M. Barrett - US grants

DESCRIPTION (provided by applicant): Spatial neglect, pathologically asymmetric spatial behavior resulting from a brain injury (Heilman, 1979) and causing functional disability (Barrett and Burkholder, 2006) may occur in 20-50% of strokes, up to 350,000 Americans annually (Ringman et al., 2004;American Stroke Assoc., 2007). Difficulty eating, dressing, and navigating in complex environments occurs acutely in this disorder, but even if symptoms improve in chronic recovery, people with spatial neglect are more likely to lose functional independence (Katz et al., 1999). Current standard clinical approaches are not theory driven, and widely-employed therapies may be only marginally effective. In this proposal, we suggest two means by which scientific acute spatial neglect treatment can be implemented. In available studies, subject heterogeneity may have obscured treatment effects. Across methods, studies used single subject, case series, and group analytic designs, but did not attempt to reconcile the distinct advantages offered by individual versus group analytic approaches. Different treatments might affect different spatial cognitive recovery functions, but simple, global outcome measures may not reflect these changes. Modeling both subject-specific and group effects is also an extremely useful method of examining targeted treatment effects. We will collect spatial neglect treatment response data over four years, for two promising and feasible spatial neglect treatments: prism adaptation training and dopaminergic medication. With mechanism-specific outcome assessment and hierarchical linear modeling, we will examine whether treatments result in predictable response. We will also examine whether controlling for subject-specific predictors models group recovery trajectory. Lastly, we will examine current standard global outcome measures instruments which have not been fully psychometrically developed, and attempt to predict subject- and group-specific recovery profiles for these variables. We hope this research will improve our ability to design cognitive rehabilitation treatment studies. It may also, however, improve our ability to translate cognitive neuroscience models of action, spatial knowledge, and attention, to treatments to optimize adaptive movement in complex environments. PUBLIC HEALTH RELEVANCE: This study investigates novel methods of outcome analysis for comparing two treatments for hidden disabilities in functional vision after stroke. We hope this research will improve our ability to design cognitive rehabilitation treatment studies. It may also, however, improve our ability to bring basic brain science to the bedside, to optimize stroke survivors'adaptive movement and balanced visual-spatial function in complex environments.

DESCRIPTION (provided by applicant): Post-stroke, functional visual problems are frequently cerebral rather than ocular. However, brain systems are not the basis of current rehabilitation. Even marginally better outcomes in estimated 230,000 US acute stroke survivors with spatial neglect could result in annual savings >$200 million. The Candidate proposed that better spatial neglect rehabilitation outcomes may result from appropriate subject stratification: performance supported by dopaminergic "aiming" systems, as well as established perceptual "where" brain networks, determined recovery in classical animal studies. With outstanding mentoring and training, under a K08 award she developed and validated a spatial neglect assessment method quantifying these recovery components. Novel K02 studies further demonstrated that "aiming" and "where" functional stratification correlated with recovery and response to clinical treatment. Continuous NIH funding since 1999 allowed her to apply the translational stratification hypothesis to neurorehabilitation research, attracting numerous clinician-researcher trainees for hands-on training. Recently, R01 funding allows her to expand her research goals, investigating translational stratification of recovery trajectory in larger groups of stroke survivors with spatial neglect. A physician cognitive neuroscientist applying psychological theory to stroke rehabilitation, she is a unique role model for medical trainees at three distinct levels. Medical students compete for research laboratory rotations, and are mentored individually in clinical research. Physiatric resident physicians are mentored in clinical research, and physiatric residents and post-doctoral fellows perform program-required research in her laboratory, resulting in trainee-authored manuscripts and presentations (5 in 2008). The K24 mechanism provides critical protected time for the Candidate to expand the theoretical basis of her clinical research, and commit appropriately to mentoring activities. The proposal activities also build her collaboration with Anne Foundas, MD. Their developing translational neuro- anatomic model, to potentially predict recovery and response to spatial neglect treatment after stroke, is expected to generate novel hypotheses for further trainee-mentor collaboration and grant applications.

Project Abstract This application seeks funding to continue our on-going investigation into the effects of intensive, high dosage task and impairment based training of the hemiparetic hand, using haptic robots integrated with complex gaming and virtual reality simulations. A growing body of work suggests that there is a time-limited period of post-ischemic heightened neuronal plasticity during which intensive training may optimally affect the recovery of gross motor skills, indicating that the timing of rehabilitation is as important as the dosing. However, recent literature indicates a controversy regarding both the value of intensive, high dosage as well as the optimal timing for therapy in the first two months after stroke. Our study is designed to empirically investigate this controversy. Furthermore, current service delivery models in the United States limit treatment time and length of hospital stay during this period. In order to facilitate timely discharge from the acute care hospital or the acute rehabilitation setting, the initial priority for rehabilitation is independence in transfers and ambulation. This has negatively impacted the provision of intensive hand and upper extremity therapy during this period of heightened neuroplasticity. It is evident that providing additional, intensive therapy during the acute rehabilitation stay is more complicated to implement and difficult for patients to tolerate, than initiating it in the outpatient setting, immediately after discharge. Our pilot data show that we are able to integrate intensive, targeted hand therapy into the routine of an acute rehabilitation setting. Our system has been specifically designed to deliver hand training when motion and strength are limited. The system uses adaptive algorithms to drive individual finger movement, gain adaptation and workspace modification to increase finger range of motion, and haptic and visual feedback from mirrored movements to reinforce motor networks in the lesioned hemisphere. We will translate the extensive experience gained in our previous studies on patients in the chronic phase, to investigate the effects of this type of intervention on recovery and function of the hand, when the training is initiated within early period of heightened plasticity. We will integrate the behavioral, the kinematic/kinetic and neurophysiological aspects of recovery to determine: 1) whether early intensive training focusing on the hand will result in a more functional hemiparetic arm; (2) whether it is necessary to initiate intensive hand therapy during the very early inpatient rehabilitation phase or will comparable outcomes be achieved if the therapy is initiated right after discharge, in the outpatient period; and 3) whether the effect of the early intervention observed at 6 months post stroke can be predicted by the cortical reorganization evaluated immediately after the therapy. This proposal will fill a critical gap in the literature and make a significant advancement in the investigation of putative interventions for recovery of hand function in patients post-stroke. Currently relatively little is known about the effect of very intensive, progressive VR/robotics training in the acute early period (5-30 days) post-stroke. This proposal can move us past a critical barrier to the development of more effective approaches in stroke rehabilitation targeted at the hand and arm.