Steven C. Cramer, M.D. - US grants

Currently, little is known about the restorative processes that occur in the brain during stroke rehabilitation. The goal of the proposed studies is to generate an improved understanding of these processes in order to refine treatments that promote stroke recovery. The proposed research will take advantage of the excellent spatial and temporal resolution of functional MRI (fMRI) to precisely measure the location and magnitude of brain restorative processes. Observed changes in brain functional organization will be correlated with neurological and functional assessments of recovery. The specific aims of the proposed research are as follows: Specific aim number 1: to test the hypothesis that fMRI of subjects with good recovery from stroke will demonstrate patterns of brain organization different from those seen in normals. Our pilot data suggest that several brain areas are recruited in subjects with good stroke recovery. The specificity of data from subjects with good recovery will be assessed by comparing these results with those obtained from subjects with poor recovery. An MRI-compatible device invented by our group will be used to measure motor performance during fMRI scanning. Specific aim number 2: to test the hypothesis that serial changes in fMRI scans correlate with serial changes in clinical status. A good correlation at the time of clinical improvement would imply that the fMRI activations are a reliable marker for effective recovery mechanisms. Continued brain reorganization after plateau of clinical course could have therapeutic implications for stroke rehabilitation. Specific aim number 3: to test the hypothesis that fMRI activations seen after a stroke occur exclusively in regions with normal cerebral blood flow and normal cerebrovascular reserve. The fMRI method to be used is dependent on a coupling between neuronal activity and vascular reactivity. Cerebrovascular disease is highly prevalent in our subjects, however, and could alter this coupling. Therefore cerebral blood flow and vasoreactivity will be evaluated to aid interpretation of the fMRI studies. The proposed studies seek to identify where restorative processes take place in the brain and at what time points during clinical recovery these processes are changing. The long term goal is to apply the findings from the proposed research to design clinical trials aimed at maximizing long term stroke outcomes. The proposed research will be performed at three sites: (1) Massachusetts General Hospital (Boston, MA) has an active stroke service, valuable for initially identifying patients and for the continued study of cerebrovascular disease. (2) Spaulding Rehabilitation Hospital (Boston, MA) has large physiatry and stroke rehabilitation services, creating an ideal setting for serially examining stroke subjects and their treatments. (3) MGH-NMR Center (Charlestown, MA), located two miles from (1) and (2), is a pioneering fMRI center.

functional ability; neural plasticity; brain imaging /visualization /scanning; multiple sclerosis; functional magnetic resonance imaging; psychomotor function; method development; pathologic process; cognition; patient oriented research; clinical research; human subject; bioimaging /biomedical imaging;

DESCRIPTION (provided by applicant): Motor deficits are common after stroke and are a major contributor to stroke-related disability. Recent studies suggest the potential to improve motor status weeks-years after stroke. The proposed study aims to use repetitive transcranial magnetic stimulation (rTMS) to modify cortical activity in patients with a history of weakness-inducing subcortical stroke. An advantage of this approach is that it is local rather than systemic. Also, if found safe and useful, rtMS might be combined with pharmacological approaches in future studies. The intervention in the current study is rTMS at a frequency (20 Hz) known to facilitate motor cortex activity. The rTMS target is the hand motor area on stroke-side motor cortex. Several studies suggest that the amount of stroke-hemisphere motor cortex active during attempted movement is of paramount importance to motor outcome. In particular, facilitating motor cortex ventral or anterior to the hand motor area is hypothesized to best facilitate motor cortex via rTMS and thereby improve arm motor status. Image-guided methods are a central feature of the proposal, and will improve the precision and reliability of rTMS application: frameless stereotactic methods will be used to target cortical stimulation. The proposed study is a phase I, 2 site, 2 dose-tier, double-blinded study with concurrent controls that will evaluate the safety of 20 Hz rTMS in the treatment of patients with hemiparesis chronically after subcortical stroke. Study entry critiera are geared towards maximum safety, for example, enrolling only those with subcortical stroke, the patient subgroup in whom this intervention is most likely to be safe. Though the primary focus of this study is safety, pilot data will be collected regarding potential clinical efficacy. As such, occupational therapy will accompany rTMS, as numerous studies have established that a plasticitypromoting intervention best improves motor outcome when accompanied by relevant motor experience. The primary goal of the proposed study is to establish the safety of this image-guided method in this population-an appropriate first step for any new therapeutic intervention. Secondarily, the study is designed to detect any possible trends towards clinical efficacy. The long-term goal of these studies is to develop a safe and efficacious method for facilitating motor cortex function in order to improve motor status of patients with stroke-related weakness.

Spontaneous recovery after stroke is generally incomplete, making post-stroke disability a highly prevalent problem. New therapies are in development to reduce disability in patients in the chronic phase of stroke. Such therapies aim to improve behavioral status not by acutely salvaging tissue but by changing function in brain elements that survive to the chronic phase. This restorative approach has the potential to reach a high fraction of subjects with stroke. Limited guidance is available for optimal prescription of such therapies. Among patients in the chronic plateau phase, which characteristics suggest potential for reducing disability with therapy, and which suggest that deficits are instead fixed? To address this issue, 108 patients who have had a stroke in the last 20 weeks and whose motor status has reached a plateau will be evaluated, in multiple domains, including demographic, clinical, radiological, brain mapping, neurophysiological, and genetic measures. A 3-week course of standardized arm motor therapy will follow, after which clinical assessments related to arm motor function will be rechecked. This study hypothesizes that the ability to predict treatment response using behavioral exam (the usual means of selecting patients in this context) is substantially improved with addition of several measures, particularly of brain injury and function. Analyses will also define an injury threshold that indicates which patients are, or are not, likely to improve with therapy. Other analyses will focus on a proposed model of learned disuse: the ability to identify those patients who are underusing brain regions that survived the stroke would aid chronic stroke therapies. One measure of particular interest is BDNF genotype. The BDNF val66met polymorphism is present in approximately 1/4th of people, has been associated with reduction in certain measures of cortical plasticity, and might be of particular importance to predicting both spontaneous and therapy-induced stroke recovery. This will be evaluated in the 108 patient therapy study, as well as a study of spontaneous recovery in 150 patients across 9 sites. Disability affects stroke patients for many years. A number of new therapies focused on CNS repair might improve this situation. However, optimal approach to applying these therapies is unclear, particularly the issue of selecting those patients most likely to respond to therapy. The overall hypothesis of the proposed study is that characterizing CNS injury and function will provide neurobiological insights useful for optimally applying restorative therapies to human patients with stroke. Such knowledge should facilitate reducing disability in appropriately targeted patients with stroke.

DESCRIPTION (provided by applicant): It is an exciting time to be an investigator in the area of brain plasticity. Years of research aimed at improving patient outcomes is reaching the point of translation into new therapies for human subjects. In the coming years there will be a great need for clinical scientists to continue this work. The current proposal focuses on this need while examining key questions in stroke rehabilitation. The main scientific focus of this grant is brain plasticity after stroke and its relationship to rehabilitation. Countless studies have characterize changes in brain structure and function after stroke and their relationship to improved patient outcomes. This area of science benefits from techniques to measure to brain plasticity in human patients, and from clinical trials to evaluate promising restorative therapies. Under the aegis of this grant, PMR residents in training, physical therapists in DPT programs, and clinical fellows will each take part in a number of research projects. Currently ongoing projects include the study of robotics to improve motor function after stroke, and the study of genetic variation influences on stroke outcomes. New research proposed herein includes evaluation of dopaminergic drugs to improve patient outcomes, implementation of bedside brain mapping in the rehabilitation ward using dense array EEG, and a study of a telerehabilitation system to reduce disability after stroke. In addition to providing more time for the PI to perform patient-oriented research and to have increased availability as a mentor, the K24 grant will also support a computer scientist and a biostatistician, both of whom provide critical skills to new investigators in patient-oriented research. The University of California, Irvine has wide-ranging resources for training of clinical investigators. Chief among these is the Institute for Clinical Translational Research, supported by an NIH CTSA grant, which has numerous offerings relevant to the mission of the current proposal, including scientific cores, bioinformatics support and nursing support. The candidate has long been committed to mentoring clinical scientists in patient-oriented research and looks forward to increasing this activity in the future.

DESCRIPTION (provided by applicant): Stroke is a major cause of disability, and the burden of stroke is increasing given increasing survival rates. Rehabilitation therapy after stroke therefore remains a major national concern, with an annual cost of several billion dollars. While rehabilitation therapy of increased intensity and duration have been firmly linked with improved patient outcomes, many patients do not receive this due to issues such as cost and access. Methods are needed to deliver stroke rehabilitation in a maximally efficient manner. A telehealth solution might be useful to address these issues. This study aims to determine if telerehabilitation is comparably efficacious with outpatient clinic therapy, using a single-blind, randomized, non-inferiority study design. The primary endpoint is the change in arm motor status from baseline to 1 month post-therapy. A pilot study found that telerehab performed well at increasing patient knowledge on stroke prevention and risk factor control. The current study will confirm this result and will determine whether these gains in knowledge extend to real world improvement in two hard endpoints relevant to stroke patient outcomes: body weight and blood pressure control. Because compliance with many forms of therapy is often limited, hypotheses related to inter-subject differences in compliance will be tested. The long-term goal of this program is to develop a comprehensive system for delivery of telerehabilitation in the home that increases access to high intensity therapy using an economically sound approach, and thereby improves patient outcomes. The current proposal is a major step in this direction.

The goal of the ICTS Mentored Career Development (MCD) program is to provide scholars with a comprehensive and cutting-edge set of research tools and leadership skills designed to help them successfully navigate a career in translational research in these challenging times. Our MCD has been structured and configured based on areas of expertise here at UC Irvine, robust collaborations with CTSA partners across the network, remarkably generous institutional support, and a faculty that has demonstrated its willingness to join us in creating this exceptional program. The program highlights five critical features. 1) Integrated Leadership?We have purposefully combined the NRSA and MCD programs under one leadership umbrella to ensure productive interaction among all of our scholars and trainees, and efficiencies in using training resources. Our NRSA and MCD leaders are also intimately involved in the overall ICTS governance and organization so that virtually all aspects of scholars? training and research are interwoven into the broader activities of our CTSA Hub. 2) Focused Flexible Accelerated Studies (FFASt)?FFASt is a new series of immersive-learning workshops designed to cover current issues in translational research. Learning opportunities are designed to shorten the formal didactic component of the training process without disrupting research productivity. Topics include: a) Implementing Team Science Best Practices, b) The Crisis of Reproducibility in Biomedical Research, c) Teachable Elements of Innovation in Biomedical Research, and c) What Every Biomedical Researcher Must Know About Community Outreach and Engagement. 3) Experiential Learning Opportunities (Real World Externships)?In collaboration with (and in the spirit of) UC Irvine?s recent successful application for an NIH BEST (Broadening Experiences in Scientific Training), scholars will have the opportunity to work in private sector CROs, drug and technology development companies, and in health and law issues in the Superior Courts of Orange County. 4) Outreach and Inclusion Excellence? Working with successful existing programs in our School of Medicine that target underrepresented minorities, scholars will teach and mentor students regarding careers in translational research. These efforts will help prepare promising individuals for successful careers in medicine and simultaneously enlarge our own candidate pool of future translational researchers. 5) Outstanding Mentorship?Learning from best practices across the CTSA Network, scholars will have the advantage of a well-trained mentorship team consisting of both experienced translational researchers and specialists in the scholar?s area of interest. The mentors and scholars undergo frequent evaluation with the goal of identifying and fixing problems in the scholar?s progress at the earliest stages. Finally, mentors and scholars will be rewarded in a number of ways, including: ICTS vouchers for research support; enhanced access and reduced recharge for informatics and statistical consultations; dedicated pilot/feasibility grants; and personal guidance in extramural grant preparation.

? DESCRIPTION (provided by applicant): Stroke continues to represent the leading cause of long-term disability in Americans. Rehabilitation therapy is provided as standard of care following stroke, as strong evidence supports that it can improve patient outcomes. However, patients show a great deal of variability in their response to post-stroke rehabilitation therapy. While a number of factors have been identified that provide insight into the basis for these inter-subject differences, overall knowledge remains limited. The proposed studies will examine how genetic polymorphisms interact with rehabilitation therapy and with stress to affect treatment-induced recovery after stroke. In this research we build on our prior work and take a unique approach to understanding therapeutic response in stroke survivors. Dr. Holman has addressed the important impact that stress and genetic susceptibilities to stress may have on well-being and health outcomes following trauma. Dr. Cramer has studied stroke recovery and its genetic influences. In collaboration with geneticists in the Center for Human Genetic Research at Massachusetts General Hospital, the team will study how stress and specific genetic factors are related to the response to rehabilitation therapy, and the maintenance of these gains over time. Variability in therapy-induced recovery after stroke is wide. The current studies may provide insight into biological factors underlying this phenomenon, and so may help individualize rehabilitation care.

Project Summary There are over 7 million stroke survivors in the US alone, with approximately 795,000 new cases annually. Despite the best available physiotherapy, 30-60% of stroke survivors remain affected by gait function impairments, with foot drop often being the primary cause. Given that post-stroke gait impairments remain suboptimally addressed, novel methods that can provide lasting neurological and functional improvements are necessary. Brain-computer interface (BCI) technology may be one such novel approach. BCI technology enables ?direct brain control? of external devices such as assistive devices and prostheses by translating brain electrophysiologi- cal signals (e.g. EEG) into control signals. When BCI systems are integrated with functional electrical stimulation (FES) systems, they can be used to deliver a novel physiotherapy to improve motor function after stroke. BCI- FES systems are hypothesized to stimulate a Hebbian plasticity process (where ?neurons that ?re together, wire together?), and this approach may lead to functional recovery after stroke beyond that of conventional physiother- apy. The applicant's preliminary research indicates that applying this technique to foot drop after stroke is safe and may improve gait function via neural processes. Hence, this warrants further investigation to: 1. determine if BCI-FES therapy can provide lasting gains in gait function in chronic stroke patients with foot drop; 2. determine what factors in?uence BCI-FES therapy; and 3. explicitly elucidate the underlying neural repair mechanisms. First, a Phase II clinical trial in patients with foot drop due to chronic stroke will compare the effect of BCI- FES dorsi?exion therapy to that of dose- and intensity-matched standard physiotherapy (Aim 1). Comparing the improvement in gait velocity and other secondary outcome measures between the two groups will test the hypothesis that BCI-FES therapy provides functional and neurological gains beyond those of conventional phys- iotherapy. It will also determine which aspects of gait impairment are best addressed with BCI-FES therapy versus conventional physiotherapy. The relationship between the subjects' baseline characteristics (gait velocity, dorsi?exion function, motor evoked potentials, electroencephalogram features, sensation) and the outcomes will determine what features in?uence responsiveness to BCI-FES dorsi?exion therapy (Aim 2). Finally, the underlying mechanism driving the neurological improvements of BCI-FES will be elucidated using an explicit computational neuroscience model of stroke recovery, informed by experimental neurophysiological measurements (Aim 3). Determining that BCI-FES therapy can provide improvements beyond that of conventional therapy may lead to a new neural repair mechanism that can be effective in stroke patients. This mechanism can inform the design of future physiotherapy techniques or improve current ones. Finally, BCI-FES therapy may ultimately become a novel form of physiotherapy to reduce post-stroke disability, and in turn reduce the public health burden of stroke.

Currently, 7 million US stroke survivors have significant disability, more than half with residual motor deficits. Motor function, particularly of the upper extremity (UE), is critical for regaining independence after stroke. UE function largely depends on integrity of motor cortex and its descending fibers, collectively termed the corticomotor system (CMS). Validated, clinically relevant biomarkers that identify biologically distinct patient subgroups are critically needed, particularly for the often affected and functionally important CMS. Their absence is a major obstacle to developing and personalizing new recovery therapies, especially in the early days post- stroke. Presence or absence of motor evoked potential (MEP) responses to TMS and extent of MRI-measured acute lesion load involving corticospinal tract (CST) are ready for formal validation. Also, the Predict Recovery Potential (PREP)-2 prediction tool, which sequentially combines acute clinical information and MEP status, is primed for multi-site validation. Our current objective, well-aligned with StrokeNet?s, is to validate the most biologically relevant and primed biomarkers of 90-day UE motor outcomes after ischemic stroke in the first large- scale, prospective, acute dataset of clinical, transcranial magnetic stimulation (TMS), and MRI measures. The central hypothesis is that patients have different UE outcomes depending on CMS function measured with TMS, and on CST injury measured with MRI. The proposed study, ?Validation of Early Prognostic Data for Recovery Outcomes after Stroke for Future, Higher Yield Trials? (VERIFY), will collect data from 657 patients at 30 US sites to address the following specific aims. Aim 1: To externally validate the relationships that TMS and MRI biomarkers of CMS integrity acquired < 7 days after stroke have with UE motor impairment outcome at 90 days after ischemic stroke. Aim 2: To externally validate the PREP2 prediction tool used < 7 days after stroke to predict 90-day UE functional outcome for individual patients with ischemic stroke. Our multi-dimensional approach to UE motor outcomes is an innovative advance on previous biomarker studies, which were typically limited to predicting outcomes in one or two domains. We will comprehensively measure UE outcomes 90 days post-stroke in three domains of motor performance ?impairment, function, and use ? identified by the World Health Organization International Classification of Functioning, Disability and Health. Our cross-disciplinary team has established expertise in multicenter acute trials, neurophysiology, neuroimaging, and stroke recovery and rehabilitation. The results are expected to have a positive impact because biomarkers used in the acute stroke period to identify patient subgroups with distinct day-90 outcomes can aid stroke recovery trials and inform rehabilitation decision-making.