David E. Vaillancourt, Phd - US grants

DESCRIPTION (provided by applicant): Functional magnetic resonance imaging (fMRI) at 3 Tesla provides a powerful tool to investigate the sensorimotor processes involved in the neural control of human movement. The long term objective of the investigator is to examine the neurophysiological processes, as measured by blood oxygenation level dependent (BOLD) contrast, involved in the motor control of healthy individuals and extend these paradigms to study the influence of intervention strategies (e.g. rehabilitation, pharmacology) on the physiology of aging and disease. The specific purpose of this proposal is to examine the neural systems underlying the spatial and temporal components of the mechanism that transfers visual signals into motor commands---a visuomotor process. The proposed studies will measure BOLD contrast fMRI and isometric force output from human participants while they perform continuous feedback-based force production. The experiments will examine two hypotheses in two specific aims. Aim 1 tests the hypothesis that the temporal component of the visuomotor process is localized in the parietal cortex and the cerebellum bilaterally. Aim 2 tests the hypothesis that the spatial component of the visuomotor process is also localized in the parietal cortex and the cerebellum bilaterally. It is further hypothesized that the spatial regions within the parietal cortex and cerebellum will be different from the temporal areas shown in Aim1. Collectively, these findings will advance our fundamental understanding of human systems neuroscience and improve feedback models of visuomotor control. These findings will have further implications for better understanding the visuomotor control deficits associated with aging, and diseased persons with Parkinson's disease, ataxia, and cerebellar deficits.

DESCRIPTION (provided by applicant): Longitudinal studies in Parkinson's disease (PD), that document how changes in structure and function of the brain relate to changes in movement and cognition, represent a critical component to developing new therapies that will slow the rate of progression of PD. Unfortunately, longitudinal studies of brain structure and function in PD are very rare. In years 7-12 of this renewal R01, our laboratory is well-positioned to conduct a longitudinal study since we have already tested 40 patients with PD and 40 age and sex-matched control subjects at baseline. Our research team has used diffusion tensor imaging (DTI) to show that the structural integrity of the dorsal substantia nigra is reduced with age, and that the ventral substantia nigra is reduced in early stage, de novo PD. Further, our laboratory has used functional magnetic resonance imaging (fMRI) to show that the functional activity of all basal ganglia nuclei are reduced in PD during specific grip force switching tasks. We have shown that the functional activity of basal ganglia nuclei relates to specific motor signs in PD, such as bradykinesia and tremor. In this renewal, we will compare our baseline DTI and fMRI data in 40 de novo patients with PD and 40 control subjects longitudinally to a 4 year time point. In year 4, patients will be tested off and on antiparkinsonian medication. We test the hypothesis that alterations in the structural integrity of the substantia nigra and anterior thalamus are linked to disease progression changes in motor signs and cognitive signs. As a consequence, disease progression changes in motor signs and cognitive signs will be related to region-specific changes in functional activity of the basal ganglia, thalamus, motor cortex, and frontal cortex in PD. Aim 1a will use DTI to examine the structural integrity of the substantia nigra in relation to motor signs of PD. Aim 1B will use fMRI during a well-defined force switching task to examine the relation between functional activity of the basal ganglia, thalamus, and motor cortex to motor signs of PD. Aim 2a will use DTI to examine the structural integrity of the thalamus in relation to cognitive signs of PD. Aim 2b will use fMRI during a cognitive-motor task to examine the functional activity of the caudate and frontal cortex in relation to cognitive signs of PD. The proposed research is both significant and innovative because it will be the first comprehensive study to use structural and functional brain imaging at 3 Tesla to focus on how subcortical and cortical brain structures change in patients with PD after 4 years.

DESCRIPTION (provided by applicant): During neurological rehabilitation following a stroke or brain injury patients may retrain the motor system using a robotic device in which they interact with a visual feedback display. Recent evidence indicates that enhancing errors may facilitate rehabilitation, and error feedback can be enhanced through visual feedback. Our long-range goal is to develop a basic understanding of how the central nervous system processes visual information during motor control, and apply this information to facilitate brain activation during neurological rehabilitation. As the first step, the objective of this four year proposal will determine how temporal and spatial features of motion stimuli differentially modulate the neuronal activation and topography of the visuomotor, visual, and motor systems within the human brain. This proposal will implement carefully- constructed motor psychophysics paradigms that we have previously established behaviorally to manipulate temporal and spatial dimensions of visual motion stimuli. At the same time, we will measure human grip force, eye movements, and brain activation using state-of-the art BOLD fMRI. Our central hypothesis is that the human visuomotor system processes temporal and spatial properties of motion stimuli through topographically organized neural mechanisms in the parietal cortex, premotor cortex, basal ganglia, and cerebellum. The specific aims are: 1) To determine how the temporal features of motion stimuli are processed in the brain;2) To determine how the spatial features of motion stimuli are processed in the brain;and 3) To determine the topographic organization and integration for temporal and spatial properties of visual motion in the brain. The innovation of this proposal is that we will provide the first comprehensive examination of the neural mechanisms of the visuomotor and motor system related to temporal and spatial features of motion stimuli. This outcome will extend what is known about the motion processing stream beyond visual cortex to regions that control movement. Furthermore, the outcome of this study will provide basic insights into how brain activation can be enhanced with visual feedback that may prove important for designing visual feedback displays used during neurological rehabilitation following stroke and brain injury. PUBLIC HEALTH RELEVANCE: This research study uses brain imaging technology to show that different parameters of visual information can facilitate brain activation in regions of the brain that control movement. This is the first step toward our long-term goal of using patient-specific visual feedback displays during neurological rehabilitation to facilitate brain activation and maximize recovery of function.

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Other movement disorders that commonly mimic symptoms of PD include the Parkinsonian variant of multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and essential tremor (ET). Taken together, these movement disorders affect over 10 million people in the United States alone. Current diagnostic approaches for PD, MSA, PSP, and ET are based on behavioral signs and clinical judgment, and this can often lead to the incorrect diagnosis, especially early in the course of the disease. In fact, it is estimated that 15% of patients in disease modifying drug trials for early PD do not have PD. Objective, valid, non- invasive, and biologically relevant markers of PD, MSA, PSP, and ET are pivotal for early and accurate diagnosis (trait), and for tracking disease progression (state). Our group has recently shown that diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) can be used to identify mechanisms for basal ganglia dysfunction in individuals with Parkinson's disease. Our preliminary data indicate that DTI and fMRI measures from the basal ganglia and cerebellum show excellent promise for differentiating PD, MSA, PSP, and ET, and for tracking longitudinal disease-specific changes in neurodegeneration. We will recruit 150 individuals for the study: 30 patients with PD, 30 patients with MSA, 30 patients with PSP, 30 patients with ET, and 30 control subjects. In Aim 1, we will use DTI and fMRI of the basal ganglia and cerebellum to focus on the development of a sensitive and specific trait marker for each movement disorder. In Aim 2, we will test the same individuals following 2 years using DTI and fMRI of the basal ganglia and cerebellum to develop state markers of neurodegeneration for each movement disorder. With the large and carefully diagnosed patient population at the Center for Movement Disorders and Neurorestoration and the state-of-the-art MRI facility at the McKnight Brain Institute, our group is uniquely positioned to complete the proposed study. The proposed research is innovative because it will utilize structural and functional imaging modalities with a 32-channel head coil performed on a state-of-the-art 3 Tesla MRI unit. The proposed research is significant because it will be the first stud to develop non-invasive trait and state markers of four debilitating movement disorders that affect over 10 million people in the United States.

? DESCRIPTION (provided by applicant): A cardinal sign of Spinocerebellar ataxia (SCA) is dysmetria, defined as endpoint errors in intended movement. A potential consequence, that has largely been unexplored, is that dysmetria contributes to functional motor deficits in SCA. Further, the neurophysiological basis of dysmetria remains poorly understood. More importantly, therapeutic interventions to reduce dysmetria in SCA are underdeveloped. Our preliminary data demonstrate that individuals with SCA6 respond to acute motor practice and are able to reduce leg dysmetria. Further, we found that leg dysmetria strongly correlates to the clinical assessment of function (International Cooperative Ataxia Rating Scale score; ICARS) and to increased motor neuron pool variability in SCA6. Finally, we found that SCA6 individuals have decreased activation of the cerebellar-thalamo-cortical circuit using functional magnetic resonance imaging (fMRI). Based on our preliminary data, we test the central hypothesis that an error-reducing intervention will decrease dysmetria in SCA by increasing the activation of the thalamus and motor cortex and reducing the variability of the motor neuron pool. To address this hypothesis we propose the following two specific aims. In Aim 1, we will determine if an error-reducing intervention can decrease dysmetria and improve motor function in SCA. To accomplish this Aim, we will recruit 30 SCA (SCA1, SCA3, SCA6) that will be assigned to an error-reduction training group (N=15) or to a best medical management (BMM) control group (N=15). We will quantify dysmetria with errors during goal- directed movements of the ankle and motor function with clinical assessments (ICARS). The error-reduction intervention will be a home-based program using a novel, custom designed computer interface. Participants will train to reduce error during goal-directed movements of the leg to targets in a 3D virtual environment. The intervention will be 4 weeks long for 4 days a week lasting 1 hour on each day. We hypothesize that the error- reducing intervention will lead to reduction in dysmetria and consequently improvements in motor function. In Aim 2, we will determine the neurophysiological changes that mediate reductions in dysmetria and improve motor function in SCA following an error-reducing intervention. To accomplish this Aim, we will quantify functional changes of the brain with fMRI and changes in motor neuron pool variability by examining the discharge rate variability of multiple motor units. We hypothesize that the error-reducing intervention will increase the functional activity of the thalamus and motor cortex and reduce motor neuron pool variability. This innovative proposal will use novel, cost effective and state-of the-art technology based intervention to address dysmetria and significantly impact the current rehabilitation of SCA.

? DESCRIPTION (provided by applicant): Movement disorders such as Parkinson's disease, dystonia, and ataxia strip away the ability to act on our environment. Each disease causes unwanted movements, makes desired movements more difficult to perform, and also affects how we think and process our emotions. To be effective, research into movement disorders must cross disciplines, and enhance the translation of basic science discoveries to help humans move more effectively. This Movement Disorders and Neurorestoration Training (MDNR) program confronts this problem head on by bringing together an outstanding group of mentors with a rich infrastructure and resources to train predoctoral Trainees focused on movement disorders. This program combines a critical mass of well-trained scientists prepared to conduct research focused on the ABC'S of translational research: an etiology, biomarkers/end phenotypes, and causative and symptom based therapies. To do so, the program will encompass three areas with a central theme of movement disorders: a) molecular biology and animal models; b) translational neuroscience and physiology, and c) human motor and cognitive neuroscience. Specific approaches within these themes can range from genetics to molecular to neuroimaging to neurorestoration to behavioral, but the central focus is movement disorders. Trainees are selected from a pool of outstanding students with diverse backgrounds and are admitted by one of five graduate programs. A key feature is that Trainees experience laboratories that cross areas, and dissertation committee members must come from each of the three scientific areas. The MDNR program capitalizes on existing strengths and strategic investments at the University of Florida (UF) including well-established investigators in ataxia, Parkinson's disease, atypical parkinsonism, and dystonia, outstanding animal research facilities for basic science, world class animal and human imaging facilities, three privately endowed and foundation supported Centers of Excellence for Parkinson's disease, dystonia, and ataxia, and the UF Center for Movement Disorders and Neurorestoration. This patient-centered clinical research facility maintains the largest, comprehensive clinical research database in the world. Upon entering the program, each trainee prepares an individualized career development plan that consists of a structured didactic program, specialized courses, seminars, and laboratory research. The mentor to mentor interaction that crosses levels of analysis sets up a unique learning environment that will prepare Trainees for a strong future as biomedical scientists that can make a difference in movement disorders. This training program in Movement Disorders and Neurorestoration provides an interdisciplinary training environment that is fundamental to the advancement of research in the etiology and treatment of movement disorders.

? DESCRIPTION (provided by applicant): The cerebellum is crucial in upper and lower limb motor control, and people with cerebellar damage can have difficulty with upper and lower limb motor functions. One form of cerebellar damage is that in spino- cerebellar ataxia (SCA) 6. It is caused by mutations in the CACNA1A gene and causes relatively pure cerebellar degeneration. The majority of the neuroimaging work in SCA-6 has used structural magnetic resonance imaging (MRI), and these studies point to degeneration isolated to the brain stem and cerebellum. Despite advances in genetic and structural MRI characterizations of SCA-6, we still do not understand how the functional brain networks between the cerebellum and cortex are affected in SCA-6. We also have yet to link specific functional changes in the brain and muscle with clinically-relevant upper and lower limb motor functions. Although structurally the thalamus and cortex may seem intact in SCA-6 patients, this does not imply that the thalamus and cortex are functioning normally in SCA-6. If the cortex and thalamus are also affected in SCA-6, this would open the door for potential therapies that either stimulate or target specific receptors in the thalamus and cortex. One advantage of task-based functional magnetic resonance imaging (fMRI) and functional connectivity is these methods will respond to acute treatments, and can provide a research and drug development platform to test new therapies for ataxia in SCA-6. The long-term goal of this work is to develop a motor physiology platform to evaluate target engagement and test novel therapies in SCA-6 and other SCAs. The first step is to understand the basic pathophysiology of SCA-6 which will be achieved in this R21. We propose to characterize: 1) the state of cerebellar, thalamic, and cortical functional activity using task-basd fMRI, 2) the functional connectivity between the cerebellum and cortex while probing circuits specific to upper and lower limbs, and 3) the activation of the motor unit pool of a hand muscle used in gripping objects and the ankle dorsiflexors which are used in lower limb motor control. We will then determine if the pathophysiology assayed across of brain and muscle relates to upper and lower limb motor functions using the International Cooperative Ataxia Rating Scale (ICARS). The outcome of this work will help us achieve our long-term goal of developing a motor physiology platform to evaluate target engagement and testing novel therapies in SCA-6 and other forms of ataxia.

? DESCRIPTION (provided by applicant): Essential tremor (ET) is a common and often progressive neurological disease with a prevalence of around 4% after the age of 40 years. More than 90% of ET patients who seek medical attention report disability. In the work setting, 15-25% of ET patients retire prematurely, and 60% choose not to seek promotion because of increased motor variability. Although ET can affect the head, voice, legs and trunk in 10-40% of cases, it affects variability of the upper limbs and hands in at least 95% of the cases. We therefore focus our research on variability during tasks involving the hand while contacting an object and producing force, because this basic task is performed during daily activities such as eating and drinking, and is negatively affected by ET. Specifically, we are interested in the interaction of visual feedback and motor variability. The proposed studies will test the novel central hypothesis that lowering the gain of visual feedback of motor output will reduce the variability of ET patients close to that of healthy adults. We plan to pursue this hypothesis because: 1) recent fMRI evidence from our laboratory indicates that visual cortex activity is increased in ET; 2) abnormal visual cortex activity is positively correlated with increased force variability; and 3) our preliminary data from individuals with ET demonstrates that reducing the gain of visual feedback substantially improves force variability. The experiments in this renewal will use multimodal imaging and electrophysiology from brain to muscle to investigate the extent of improvement, and exactly how low gain feedback reduces motor variability in ET. Our preliminary data using task-based fMRI, high-density electroencephalography (EEG), deep brain stimulation of the thalamus, and multi-motor unit oscillations provides insight into the physiology supporting the central hypothesis. Aim 1 tests the central hypothesis using fMRI, which has superb spatial resolution, across the visual cortex, cerebellum, thalamus, and motor cortex. Aim 2 tests the central hypothesis using high- density EEG and cutting-edge 3D cortical imaging analyses, which has high temporal resolution, across visual cortex and motor cortex. Aim 3 tests the central hypothesis by using deep brain stimulation to stimulate the thalamus, which is a key structure that facilitates visually-guided movement, while measuring multi-motor unit action potentials of hand muscles. This collection of systems neuroscience techniques represents an innovative approach to maximize both spatial and temporal resolution and reveal novel mechanisms from brain to muscle underpinning how low gain visual feedback reduces motor variability in ET.

Magnetic resonance imaging (MRI) is the most widely used diagnostic imaging tool for detecting neurodegenerative disorders such as Parkinson's Disease. This project will develop new automated methods for detecting subtle effects that can be revealed by MRI, including changes in water diffusional properties of human brain tissue, and functional brain activity. To assess the deviation from the normal brains, a computationally efficient algorithm will be developed to construct a population-specific brain structural template from a normal brain population. Further, a new algorithm will be developed to facilitate the detection of Parkinson's using diffusion MRI data. Finally, novel algorithms for establishing the correlation between the information derived from diffusion and functional MRI data will be developed, enabling prediction of functional activity given the anatomical information and vice-versa. Inferring such a correlation will make it possible to predict functional changes due to changes in tissue microstructure caused by neurodegenerative disorders and vice-versa.

In summary, the precise project goals are: (i) To develop a computationally efficient template brain map construction algorithm for features derived from diffusion MRI. In this context, the ensemble average propagator (EAP), which captures both orientation and shape information of the diffusion process at each voxel in the diffusion MRI data, is proposed. Validation of the constructed template will be performed using standard evaluation metrics for template-based segmentation. (ii) To develop novel methods to automatically discriminate between control and Parkinson's groups using the EAP fields as well as Cauchy deformation tensors (that capture the changes in EAP fields). Validation of the classifier will be achieved using the standard leave-k-out strategy. (iii) To develop a novel algorithm for kernel-based nonlinear regression between EAP fields derived from diffusion MRI and scalar-valued fields derived from functional MRI activation maps. The algorithm will be able to predict the level of activation given the EAP fields and vice-versa. These predictions will be validated using a priori labeled data sets. Predicting functional responses from structural information and vice-versa will significantly impact treatment planning of patients with Parkinson's Disease and other neurodegenerative disorders. The multidisciplinary nature of this project will provide the opportunity to collectively train graduate students from diverse backgrounds in the STEM related fields of this project.

PROJECT SUMMARY The goal of this application is two-fold. First, we will test and validate across two imaging sites a set of diagnostic and progression biomarkers we have recently published that differentiate and track disease progression in Parkinson's disease (PD), parkinsonian variant of multiple system atrophy (MSAp) and progressive supranuclear palsy (PSP). Second, we will use a set of novel imaging biomarkers to further understand the neurobiology of how each of these three diseases differ and progress over time. With respect to goal 1, over the past 5 years our group has led the efforts in magnetic resonance imaging (MRI) for the Parkinson's Disease Biomarker Program (PDBP) and has developed 2 innovative biomarkers for differentiating PD, MSAp, and PSP. Both free-water diffusion imaging and task-fMRI have uncovered clear patterns of degeneration and abnormal functional activation in the basal ganglia and cerebellum that can reliably differentiate PD, MSAp, and PSP. In longitudinal studies we found that free-water diffusion imaging and task- fMRI track progression of PD, MSAp, and PSP over one year with no changes in age and sex matched controls. Reproducible, reliable, objective and validated MRI-based progression markers are of great significance and would transform clinical trials in PD, MSAp, and PSP. With respect to goal 2, in addition to evaluating free-water and task-based fMRI using our standardized protocol across two imaging sites, we will also test new biomarkers that leverage advanced imaging pulse sequences using simultaneous multi-slice imaging for acquiring data faster and at a higher spatial resolution. Such technical advances provide a richer examination of the nigrostriatal, cortico-striatal, and cerebellar-thalamo-cortical anatomical tracts for disease differentiation, and for understanding how the disease spreads along disease-specific tracts over time. Leveraging simultaneous multi-slice imaging will facilitate multi-shell diffusion imaging models for examining free-water, neurite density and orientation dispersion, as well as task-fMRI connectivity for examining the functional connections across a network. At our two imaging sites, we will acquire data on 100 PD, 50 MSAp, 50 PSP, and 50 healthy age and sex matched controls. We will provide timely data sharing with the PDBP community. We have a very experienced team of experts in neurology and neuroimaging, and a long history of publishing together in high impact journals.

SUMMARY: Biomarker Core Alzheimer?s disease (AD) classically develops in the elderly. The classical way to confirm an AD diagnosis is the presence of amyloid deposition and tau pathology at post-mortem; however in-vivo biomarkers can serve as proxies of these characteristics and are invaluable in separating healthy aging from AD as well as placing individuals along the AD continuum. The Biomarker Core works closely with the three Clinical Core sites across Miami and Gainesville, as well as the Data Core to provide timely access to raw, pre-processed, and post- processed data. The Aims of this Biomarker Core include: 1) Web-based Neuroimaging Portal for Accessing, Visualizing, and Sharing Multimodal Imaging Data. 2) Integrating New Imaging and Biofluid Modalities into the Neuroimaging Portal. 3) Multimodal, Multiclass, and Machine Learning Algorithms of Imaging and Biofluid Markers. 4) Provide Support for Ongoing and Future R01, U01, REC, K01, K99, T32, and F32 grants across the network of Florida and non-Florida Projects. There is a rich and expansive group of grants that will be able to leverage the biomarker datasets acquired within the Clinical Core, including those funded as part of the Research and Education Core (REC). This core will provide the needed communication, data sharing, analysis support, and neuroimaging training for research in these projects to proceed. We believe that this study, which would be one of the largest of its kind, will combine data acquired at the Wien Center for Alzheimer?s Disease and Memory Disorders, UM Center for Cognitive Neuroscience and Aging, and University of Florida. Access to this new multimodal dataset in AD and other dementias will provide added statistical meaningfulness in studying dementia and inclusion of a large number of Hispanics and African Americans, which is much needed given the current demographics of the popular ADNI database.

SUMMARY We have known for some time that ?-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson?s disease (PD), multiple system atrophy, and dementia with Lewy bodies. People with synucleinopathies desperately need disease modifying therapies, that either slow or stop neurodegeneration. In order to facilitate the development of new therapies, the fields of neurology, motor control, neuroimaging, and ?-synuclein biomarkers need to join forces to identify disease far earlier, well before a neurologist currently makes a diagnosis. In Alzheimer?s disease, investigators have defined Mild Cognitive Impairment (MCI) before dementia and this has unleashed a series of preclinical behavioral, imaging, and pathologically-relevant markers that have revolutionized how clinical trials are conducted for dementia. This same type of revolution in early identification is sorely missing, but clearly needed, in the area of Parkinsonism. In this proposal, we will define a Mild Parkinson Impairment (MPI) using innovative markers that cut across imaging and physiology. We will study a preclinical model of Parkinsonism, known as rapid eye movement (REM) behavior disorder (RBD). The reason RBD is a preclinical model of Parkinsonism, is that 50-60% of patients with RBD go on to develop PD, and the remainder develop either dementia with Lewy bodies or multiple system atrophy. Individuals with RBD will eventually exhibit clinical Parkinsonism with varying degrees of severity. Here, we test the central hypothesis that we can identify early cross-sectional and longitudinal markers of Mild Parkinson Impairment in patients with RBD. Our goal in this proposal is to study patients with RBD prior to other diagnoses to identify early cross-sectional and longitudinal markers of preclinical Parkinsonism. Based on our strong preliminary data and our prior work we will: 1) evaluate innovative measures of brainstem functional magnetic resonance imaging and task-based striatal-cortical functional connectivity; 2) test our robust marker free-water in the substantia nigra in RBD for the first time; 3) measure a newly developed ?-synuclein skin biomarker called real-time quaking-induced conversion (RT-QuIC) assay; 4) evaluate motor control assays to define a preclinical mild motor impairment; and 5) follow patients longitudinally after 24 months to determine if these imaging and physiology markers progress over time in people with RBD.