John W. Krakauer, M.D. - US grants

The proposed award is designed to develop the candidate's clinical research skills to prepare him for a career as an independent investigator in the application of motor psychophysics and functional brain imaging to the study of neurological disease. Research Plan: Stroke, Huntington's disease (HD), and Idiopathic Torsion Dystonia (ITD) are diseases that rob people of motor function in the prime of life. Many of the measures of motor performance and functional status commonly used in clinical trials and rehabilitation suffer from subjectivity and lack of scientific validation. The first goal of the proposed study is to characterize and quantify the motor deficit in these diseases using methods previously developed in the study of arm movements in normal subjects. In particular, we will emphasize the importance of examining motor learning abnormalities because we hypothesize that these will give a direct measure of a patient's capacity to compensate or recover from neurological disease. The second goal is to correlate psychophysical parameters of motor performance and motor learning to the degree of expression of brain networks as revealed by functional imaging. This will provide considerable insight into the brain mechanisms underlying abnormalities in motor control. HD and ITD each have an established genetic basis allowing asymptomatic carriers to be identified. Our preliminary studies indicate that these subjects have psychophysical and network abnormalities even though more conventional assessments fail to find any evidence of neurological disturbance. If we confirm and extend these observations, then we will have the tools to follow therapeutic intervention at the earliest stages of disease. In the long term, we hope that our work will lead to the development of a battery of motor tasks that, in conjunction with functional imaging, will be applicable to any neurological disease. This battery will quantify motor deficits; allow monitoring of therapy; provide insight into brain mechanisms: and may serve a rehabilitative function. Educational Plan: By completing this project, I will accomplish six main educational objectives: (1) The design and application of motor psychophysics to neurological disease; (2) Learning PET imaging techniques; (3) The development of skills in brain network analysis and modeling; (4) Learning advanced statistical methods; (5) Learning the principles of functional magnetic resonance imaging; (5) Learning to conduct ethical scientific research, collaborate with colleagues, and produce high quality presentations and publications; and (6) Learning to place experimental findings within their clinical context, and relate them to clinical assessments.

DESCRIPTION (provided by applicant): Approximately 80% of stroke patients experience acute hemiparesis and approximately 40% have chronic hemiparesis. This impairment significantly limits functional use of the arm. Traditionally, hemiparesis has been characterized by weakness, spasticity and unwanted synergies. These abnormalities are usually assessed using clinical scales. Here we propose to approach the problem of hemiparesis from a more quantitative and modular motor control perspective. Our previous work, investigating planar reaching movements in healthy young subjects, demonstrates that accurate reaching depends en two types of visuomotor transformation. The first transforms a visual target into a planned trajectory in vectorial space centered at the hand with independent specification of direction and extent. This spatial transformation requires the learning of a task-specific reference frame and scaling factor. Once a plan in extrinsic coordinates is determined, a second transformation generates the required torques in intrinsic (joint) coordinates. This dynamic transformation requires learning of the biomechanical properties of the limb. The principal hypothesis of this proposal is that patients with hemiparesis have impairments in using and learning visuomotor transformations. Our secondary hypotheses are that there will be differential impairments in these visuomotor transformations depending on whether the dominant or non-dominant arm is affected and on lesion location. We will include patients who are six months or more out from their first stroke with clinically demonstrable arm weakness at stroke onset. All patients in the study will have had a structural brain MRI with diffusion and perfusion-weighted imaging. Patients with more than one lesion or inability to follow instructions will be excluded. Patients (and age-matched controls) will perform planar reaching movements with their arm supported on a horizontal surface to eliminate gravity. Hand position and joint angle data will be obtained using a magnetic recording system. Motor learning will be assessed by having subjects adapt to a cursor rotation or a laterally-placed mass. Lesion location will be determined by a neuroradiologist. Confirmation of common lesion locations across patients will be made by transforming the T1 images into Tailarach space using SPM2. Our findings will contribute to a mechanistic understanding of hemiparesis, suggest novel rehabilitation strategies and help find better measures of recovery.

[unreadable] DESCRIPTION (provided by applicant): The overall goal of this study is to use continuous arterial spin labeling, CASL, perfusion MRI to characterize diaschisis and determine its contribution to hemiparesis after subacute stroke. Stroke remains the leading cause of death worldwide despite improvements in acute stroke treatment and prevention. Patients show considerable variability in the degree to which they recover and the mechanisms underlying this variability are still largely unknown. One mechanism, termed diaschisis, was proposed almost a century ago to explain part of the initial deficit and the ability to partially recover from it. Diaschisis refers to a reduction of cerebral blood flow in uninjured brain regions that are connected to the area of injury. Animal models suggest that the reduction in cerebral blood flow is the result of decreased neuronal activity in the connected areas. Within this framework, the initial deficit is due to combination of diaschisis and the loss of function at the lesion location, whereas recovery occurs as diaschisis reverses. Previous attempts to study this phenomenon in humans have relied on PET and SPECT, which are expensive, not widely available, and require injection of radioactive tracers, limiting the frequency and practicality of use. As a result, there have been relatively few studies of diaschisis and thus its relevance to stroke deficit and stroke recovery remains to be determined. Here we propose to use arterial spin labeling, ASL, to investigate diaschisis in patients in the subacute and then chronic phases after hemiparetic stroke. ASL is non-invasive MR method that quantifies blood flow. To date it has been used to measure cerebral blood flow, CBF, that has been compromised by vascular occlusive disease. Here we propose a novel application of ASL for detection of decreases in CBF due to reduction in neuronal activity. The main aim of this grant is to demonstrate reductions in CBF in the contralateral cerebellum (crossed cerebellar diaschisis) and in the contralesional hemisphere. We will then correlate these changes with initial motor deficit in 3 to 4 weeks after stroke and with degree of recovery at 6 months. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): It is well known that most movements improve with practice. However, the way the brain accomplishes this remains largely unknown. Functional magnetic resonance imaging (fMRI) has provided significant insights into brain mechanisms of cognition. In comparison, fMRI studies of motor learning and motor memory have been limited by the constrained space and the problem of unwanted head movements. As a result the great majority of fMRI studies of motor learning have investigated sequences of finger movements. To overcome these limitations, we have developed a novel MR-compatible wrist task to study two types of motor learning that undrlie our ability to accurately point to visual targets: (1) Motor skill learning - the ability to acquire new patterns of muscle activity so that movement accuracy increases without a reduction in speed. (2) Visuomotor adaptation - the ability to associate an already learned pattern of muscle activation with a new spatial goal. We will study these two types of learning with a baseline and a rotation condition, respectively. In the baseline condition, subjects make fast uncorrected pointing movements of the wrist to a series of 8 targets arrayed on a screen. Skill is the decrease in movement time (MT) and endpoint variability with practice. In the rotation condition, with the same target set, subjects initially make systematic 30[unreadable] directional errors, which they reduce through adaptation. Importantly, we have developed a method that keeps MT and peak velocity constant so that any observed brain activation changes are attributable to learning and not performance changes. In addition, we will also examine the neural correlates of re-learning on a second day, differences between the dominant and non-dominant hand, mechanisms of motor interference, and degree of transfer of motor learning between arms. A better understanding of hemispheric contributions to motor learning and motor memory will offer insight into mechanisms of recovery after focal brain injury. We anticipate our approach will be applicable to patients in future studies.

Whether stepping on the brake pedal when a hazard appears in the road ahead, beginning a sprint in response to the starter's pistol, or reaching to catch a tipping glass, we possess a remarkable ability to respond rapidly and accurately to demands for action. These responses occur within a reaction time of around 250 milliseconds, during which we must perceive the need to act, decide precisely what action to take, and generate motor commands to coordinate the activity of dozens of muscles to make the movement. It is currently not clearly understood what steps in this pathway take the greatest amount of time, which brain regions are responsible for which computations, and whether or not the reaction time could be reduced even lower. With support from the National Science Foundation, Dr. John Krakauer and colleagues Dr. Adrian Haith, Dr. Pablo Celnik and Dr. Joshua Ewan will use innovative behavioral experiments with human participants to stress the limits of the reaction time and tease apart its constituent processes and limitations. They will record brain activity during these same tasks (using EEG) in order to identify the underlying brain networks responsible and will apply non-invasive brain stimulation to establish the specific function of these brain networks in generating rapid motor responses.

A number of neurological disorders, such as Parkinson disease, are associated with slowing of motor responses. Such symptoms are not well-understood at present. The knowledge gained from this study will yield important insights as to why this slowing may occur and what, if anything, could be done to treat it from a therapeutic and/or clinical perspective. A deeper understanding of the reaction time will also be of significant interest to those seeking to push the limits of human performance, such as athletes and race car drivers, or amateurs seeking to better their own performance. Furthermore, data collected in this study are likely to be of broad interest and therefore will be made available to other researchers. EEG recordings will be of particular interest to researchers developing advanced analytical techniques for mapping human brain activity. Finally, students from under-represented minorities, including those from economically disadvantaged backgrounds, will have the opportunity to directly participate in this project and gain valuable research experience through the Johns Hopkins Diversity Summer Internship Program.