Jerrold Vitek - US grants

Recent anatomic and physiologic studies have demonstrated that the areas of the ventrolateral (VL) thalamus which receive output from the cerebellum (VPLo) and basal ganglia (VLo) are discrete and non- overlapping and that these thalamic subregions project to separate cortical areas. These data suggest the existence of parallel, functionally segregated, thalamocortical circuits which subserve different roles in motor control and the expression of abnormal movements. To test this hypothesis we will examine the physiologic properties of these thalamic subnuclei and the changes associated with cerebellar tremor in the monkey cerebellar tremor subnuclei and the changes associated with cerebellar tremor in the monkey cerebellar tremor model, using quantitative behavioral assessment, single cell recording and microstimulation in the monkey VL thalamus. Cerebellar tremor will be produced by fiber-sparing lesions in the dentate nucleus. We will also assess the effects of fiber-sparing lesions of specific VL subnuclei on motor performance in both normal monkeys and the monkey model of cerebellar tremor. In parallel with the studies in the monkey, we will examine, in humans with cerebellar tremor, the effects of thalamotomy on motor performance and tremor and compare these findings to those in the monkey. These experiments will employ: 1) a passive displacement behavioral paradigm to assess muscle tone, long-latency reflexes, tonic reflexes, and neuronal responses to sensory inputs; 2) a visuo-motor step-tracking task to assess reaction time, movement time, velocity and acceleration profiles, scaling and timing of EMG activity and task-related neuronal activity. These studies will provide a firm test of the hypothesis of functionally segregated circuits, clarify the differential role of VL subnuclei in motor performance and tremor, and provide greater insight into mechanisms which underlie both normal and abnormal movements. These studies may lead to the development of new therapeutic strategies for the treatment of movement disorders.

The overall aim of this proposal is to examine the role of the ventrolateral (VL) thalamus in the development of parkinsonian motor signs and drug-induced dyskinesia. It has recently been demonstrated in the monkeys MPTP model of Parkinson's disease (PD) that neuronal activity is increased in the subthalamic nucleus (STN) and globus pallidus, pars interna (GPi) and that inactivation or lesioning of either STN or GPi reverses all the major motor signs of PD. Based on these finding it has been postulated that parkinsonian motor signs occur as a result of excessive (inhibitory) output from the GPi which acts to inhibit the motor thalamus ventralis lateralis, pars oralis (VLo). Conversely, it has been demonstrated that neuronal activity in GPi is decreased in L- Dopa-induced dyskinesia in the MPTP monkey model of PD, and it has long been known that lesions in the STN, which results in decreased inhibitory output from GPi, produce a hyperkinetic state. Thus, a model of hypo/hyperkinetic movement disorders has developed in which the motor thalamus, the primary target of efferents from the basal ganglia, plays an integral role in the development of parkinsonian motor signs and drug- induced dyskinesias. Although the evidence in support of this model is compelling at the level of STN and GPi, at present there is no evidence at the thalamic level in primates to support or refute its predictions. A role for the thalamus in mediating these disorders is supported by results in humans undergoing stereotactic surgery for PD, since lesions in VL are reported to alleviate rigidity, tremor and drug-induced dyskinesia. These observations, however, are not consistent with the hypothesis that decreased activity of thalamic neurons results in parkinsonism, since lesions in the thalamus would further reduce thalamic activity and should exacerbate parkinsonian signs. An alternative explanation is that excessive inhibition not only decreases but alters neuronal activity in the thalamus and its is this altered activity which leads to the development of disordered movement. Results from human thalamotomies, while supportive of this hypothesis, are controversial, since histologic verification of the lesions site is seldom possible. As a result, it is unclear where the lesions are actually placed, where the optimal lesion site is, if the most effective site varies for different parkinsonian signs as reported by many surgeons, or if thalamic lesions are effective in alleviating akinesia, as sign which has been reported to remain the same worsen or improve following thalamotomy. This study is designed to test the current working model of hypo- and hyperkinetic movement disorders at the level of the thalamus using the technique of single cell recording to examine the changes in neuronal activity of the motor thalamus in animal models of PD and drug-induced dyskinesia both before and after fibersparing (FS) lesion in the GPi. This study will also test the model by studying the effects of reversible and permanent FS lesions of different thalamic sub-nuclei to examine the differential role of these subnuclei in the mediation of parkinsonian motor signs and drug-induced dyskinesias. These studies will provide important information regarding the role of the thalamus in the pathophysiology of PD and dyskinesia, refine the current model of hypo and hyperkinetic movement disorders, as well as improve our understanding of the role for thalamotomy in the surgical treatment of these disorders.

DESCRIPTION: The objective of this study is to examine the correlation between the discharge of pallidal neurons and three other measures: 1) clinical motor signs; 2) metabolic activity of cortical and subcortical structures at rest (in the absence of voluntary movement); and 3) metabolic activity of the same structures during movement. Clinical motor signs will be measured preoperatively, during the pallidotomy operation, and 12 months postoperatively. Preoperative measures will include motor measures of the CAPIT protocol plus assessment of reaction time and time to complete a simple tracking class. In the operating room, bradykinesia will be assessed by timing hand movements made with the hand in a "data glove" and shoulder movements made with the arm in a manipulandum. Tremor will be assessed using an accelerometer attached to the tremulous limb. Rigidity will be assessed as the displacement produced by a torque perturbation of the wrist and shoulder. The hypotheses to be tested are: 1) the presence and severity of bradykinesia will be most closely related to increased mean discharge rate in GPi (and perhaps to an increased incidence and decreased specificity of responses to somatosensory stimulation), while tremor will be associated with an increased incidence of rhythmic bursting activity in GPi; 2) the presence and severity of rigidity will be correlated with increased mean pallidal discharge in areas different than those with high activity associated with bradykinesia; and 3) in patients who receive liquid Sinamet (l-DOPA) in an amount sufficient to produce an "ON" state during intraoperative recording, GPi neurons will have a decreased mean firing rate, a decreased incidence of bursting, and a reduction in the incidence and distribution of somatosensory receptive fields, compared to those who do not receive Sinamet, and these changes will correlate with the clinical symptomatology in the "ON" vs. the "OFF" state. The differences in neural activity recorded in the different conditions (patients who are akinetic/rigid or akinetic non-rigid, each studied either in the "OFF" condition, or in the Sinamet-induced "ON" condition) will be compared to the differences in cortical metabolic activity, as assessed with PET using the same behavioral tasks.

The proposed studies of this Center grant are focused on basic issues concerning the pathophysiology of Parkinson's disease (PD) and their therapeutic implications. These studies are, in part, concerned with animal models of PD and key aspects of the current basal ganglia- thalamocortical circuit models of parkinsonism. Project 1 is focused on the development of a more appropriate model of PD, in particular, one that exhibits the progressive nature of PD. The proposed model employs chronic systemic inhibition of complex I by rotenone in rodents with possible extension to primates. The conceptual connective framework for projects 2-5 is the exploration and testing of the current circuit model in both animal models and patients with PD. The studies in Project 2 explore in patients with PD the effects of deep brain stimulation (DBS) of the internal pallidum (GPi) and subthalamic nucleus (TN) on behavior and brain activation of 0-15 PET. These studies will help clarify functional correlates of the amelioration of specific parkinsonian symptoms by DBS of GPi and STN. Project 3 explores, in the primate metabolism in the thalamocortical circuit using a combination of single cell recording and FDG PET. Microdialysis combined with DBS of the STN will help to clarify the mode of action of DBS. This project will also examine the potential neuroprotective effects of STN inactivation. Project 4 explores key controversial issues regarding the pathophysiology of PD using microdialysis in primates. Metabotrophic glutamate receptors are abundant in STN and GPi and specific subtypes may be promising therapeutic targets. Project 5 will test the hypothesis that specific subtypes of metabotrophic glutamate receptors may play a therapeutically relevant role in PD. The Center will also provide state-of-the-art, multi-disciplinary training of fellows in research into parkinsonism and related conditions with an emphasis on translational.

The major aim of this study is to carry out a prospective, randomized clinical trial of deep brain stimulation (DBS) in the internal segment of the globus pallidus (GPi) and subthalamic nucleus (STN) for the treatment of advanced Parkinson's disease (PD). Medical therapy is the mainstay of treatment for patients with PD. After several years of drug therapy, however, a large proportion of patients experience worsening of their parkinsonism and develop incapacitating motor fluctuations and dyskinesias. To deal with this, attention has been directed to surgical procedures, especially ablative therapies, e.g. pallidotomy, and more recently deep brain stimulation (DBS). DBS mimics the effects of ablation, but is reversible. It also has the advantage in that one can adjust stimulation parameters to physiologically change the area of inactivation and to implant both sides without the high incidence of complications associated with bilateral pallidotomy. In recent years DBS in the STN and GPi has been explored in pilot studies for the treatment of patients with advanced PD. Only a few nonrandomized studies examining the effect of DBS in the STN and GPi have been performed, however, and the results, although promising, have been highly variable. This study, which follows upon our current NIH supported randomized clinical trial of pallidotomy versus medical management for PD, will comprehensively evaluate the effects of DBS in GPi and STN on motor, neuropsychological and psychiatric function, and quality of life in patients with PD. The current proposal offers the unique opportunity of using the current cohort of patients in the pallidotomy for PD clinical trial for comparison to DBS. This study will address three key issues: 1) whether there are significant differences between GPi-DBS, STN-DBS and GPi pallidotomy. 2) which patients are the best candidates for DBS and 3) whether bilateral stimulation (GPi or STN) is superior to combined GPi pallidotomy and DBS. Overall, these studies will provide important data on the short and long term effects of DBS in the STN and GPi on motor, cognitive and psychiatric functioning and quality of life in parkinsonian patients and provide much needed guidelines regarding patient selection and optimal surgical approach.

The aim of this study is to assess the effect of deep brain stimulation (DBS) within different nodal portions of the basal ganglia-thalamocortical circuit, i.e., the internal and external segments of the pallidum (GPi and GPe) and subthalamic nucleus (STN), on parkinsonian motor signs (PMS) in MPTP treated monkeys. Deep brain stimulation is increasingly being used for the treatment of patients with medically refractory Parkinson's disease (PD). This has occurred as a result of the success of DBS in the thalamus for amelioration of both parkinsonian and essential tremor and because of the increased risk of significant complications associated with bilateral ablative procedures, currently used for the treatment of PD, i.e., pallidotomy and thalamotomy. Implantation of DBS devices in the STN and GPi have recently been used to treat the signs and symptoms of PD. Results, however, have been variable, with some centers reporting 60-90 percent improvement, while others report no significant change in PMS. A number of questions regarding the use of DBS for the treatment of PD remain. The optimal site is unclear and the mechanisms underlying its effects are not known. There is an urgent need for a controlled study to assess the effects of DBS on PMS in the MPTP monkey model of PD where detailed, quantitative evaluations of DBS can be conducted in different sites in the pallidum and STN (current targets in humans) and the physiologic effects of DBS on neural and metabolic activity in the pallido- thalamocortical circuit can be evaluated. In this study, single unit recording techniques and 18F- fluorodeoxyglucose (FDG) PET studies will be employed to assess the effect of DBS on mean discharge rates and metabolic activity of specific sites within the pallido-thalamocortical circuit. In addition, quantitative measures of motor performance will be obtained during a variety of behavioral paradigms including step- tracking, torque perturbation and reach and retrieval tasks. Parkinsonian motor signs will also be assessed using established non-human primate clinical rating scales, computer assessments of spontaneous activity, as well as quantitative measures of rigidity, tremor and bradykinesia. These will be obtained in the normal and parkinsonian state and in the parkinsonian state following fiber sparing lesions in the GPe both prior to and during DBS in the STN and GPe as well as anterior (nonmotor) and posterior (motor) portions of Gpi. This study will compare the relative efficacy and determine the optimal location for DBS within the STN and anterior and posterior portions of the pallidum to maximally alleviate PMS in MPTP treated parkinsonian monkeys. In addition, this study will characterize the mechanism(s) underlying the effect of DBS in the pallidum and STN on PMS using single cell recording techniques and 18F-fluorodeoxyglucose (FDG) PET studies together with fiber sparing lesions in the GPe to further examine the role of GPe in the development of PMS and in mediating the effect of DBS on these signs.

The common goals of this program project are to understand how the basal ganglia contribute to the control of sensorimotor functions and to assess the pathophysiologic basis of human parkinsonism. The three research projects in this proposal are conceptually framed by the model of basal ganglia function formulated by DeLong and colleagues. In this model, widespread cortical inputs ultimately converge in the globus pallidus. Inhibitory pallidal output project to thalamus and brainstem. This concentrated will be an integrated investigation of basal ganglia sensorimotor function using two physiologic approaches (direct single unit recording at the neural level and PET functional imaging of regional brain activity) applied across four clinical states (normal, dopamine deficiency of Parkinson's disease (PD), dopamine replacement of PD, and surgical pallidotomy for PD). These groups will be assessed with consistent sensory, motor and control states. The experiments are distributed among three research projects, supported by two cores; one to manage subject recruitment and the other to orchestrate data analysis and modeling. The human imaging studies of this proposal form a critical bridge between the animal model of parkinsonism and clinical application of techniques such as pallidotomy to PD patients. They provide a large scale perspective of adaptation in the setting of neurodegeneration and reorganization after surgical pallidotomy that cannot be examined at the single unit level, by imaging on-human primates or behavioral assessment alone. The results could directly impact on the rational design of surgical therapies for patients with movement disorders. Integration of the imaging and physiologic data could be used to optimize lesion localization in surgical pallidotomy. Correlation of the physiological data could be used to optimize lesion localization in surgical pallidotomy. Correlation of the physiological data could be used to optimize lesion localization in surgical pallidotomy. Correlation of the physiological data with clinic scores may establish if functional imaging or intraoperative recording are reliable predictors of patient outcome.

DESCRIPTION (provided by applicant): Over the last decade, the outlook for patients with advanced parkinsonism and other movement disorders has been revolutionized by the introduction of deep brain stimulation (DBS) in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) as a highly effective treatment modality. According to recent estimates over 2000 patients with PD have undergone implantation of DBS electrodes for the treatment of PD and over 15,000 patients per year may be candidates for this procedure. This number will increase, as the use of DBS as treatment of brain disorders becomes more widespread. Despite their widespread use, very little is known about the physiologic effects of DBS. Given the somewhat similar effect of lesions and stimulation in STN, GPI and thalamus on parkinsonian motor signs, it has been speculated that stimulation may act similar to lesioning, by blocking neuronal activity. Several studies have supported this view reporting suppression of neuronal activity in the site of stimulation. Our preliminary results, as well as the results of other groups have suggested that stimulation may, in fact increase output from the stimulated structure, demonstrating that stimulation in the STN increases neuronal activity in the GPi, while GPi stimulation suppresses neuronal activity in the thalamus. Additional support for this hypothesis is derived from microdialysis studies that found increased levels of glutamate in the entopeduncular nucleus (the rodent equivalent of GPi in primates) during STN stimulation. Conceivably, stimulation of basal ganglia activity may improve parkinsonism simply by regularizing pallidal discharge patterns. Both activation and inactivation could, in fact, be invoked during stimulation, because electrical stimulation may inhibit neuronal activity, while activating fibers in the stimulated area. For further optimization of current DBS protocols, and to minimize risks and side-effects of DBS implantation, it is mandatory that a solid understanding of the mechanism of action of this intervention is developed. This study will determine the mechanism underlying the effects of DBS of STN and GPi by examining in the MPTP monkey model of PD: 1) the effect of stimulation in the STN and GPi on neuronal activity and on neurotransmitter release in different portions of the basal ganglia-thalamocortical circuit, 2) the role of GPe in mediating the effect of stimulation in the STN and GPI, in mediating the development of parkinsonian motor signs and as an alternative site for stimulation for the treatment of PD and 3) determine the effect of stimulation in the STN and GPI on cortical function. The experiments will use a combination of single cell recording, microdialysis, and 18F-fluoro-deoxy-glucose (FDG) PET studies. DBS will be accomplished by implantation of a downscaled version of DBS leads used in humans.

nervous system disorder therapy; human therapy evaluation; electrostimulus; Parkinson's disease; brain electronic stimulator; brain disorder chemotherapy; subthalamus; thalamic nuclei; lenticular nucleus; patient oriented research; clinical research; human subject;

? DESCRIPTION (provided by applicant): The goal of this study is to identify the specific neurophysiological changes that occur within and across key nodal points of the pallidothalamocortical motor circuit with the onset of Parkinson's disease and how these evolve as motor signs become increasingly more severe. This will be done by simultaneously recording and comparing the activity from populations of neurons across multiple nodal points in the basal ganglia thalamo-cortical motor circuit at rest and during movement during normal, mild, moderate and severe stages of parkinsonism in the same monkeys using sequential, low dose administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). Structures that will be examined include the primary and supplementary motor cortices, the premotor cortex, the internal and external segments of the globus pallidus (GPi and GPe, respectively), the subthalamic nucleus (STN), and the motor thalamus including ventralis anterior, ventralis lateralis pars oralis, and ventralis posterior lateralis pars oralis. Specific ims 1 and 2 will characterize changes in synchronized oscillations, bursting patterns, receptive field properties and phase amplitude coupling across basal ganglia- cortical and thalamo-cortical regions, respectively, with the animal at rest and during both passive movement and the performance of a trained motor task. Specific aim 2 will further examine the differential role of subnuclei of the motor thalamus in the development of bradykinesia/akinesia, rigidity and tremor through the application of discrete, fiber-sparing lesions. Specific aim 3 will use LFP recordings across the pallidothalamocortical circuit to characterize changes in effective connectivity between the pallidum, STN, motor thalamus and PMC, SMA and MC as a function of parkinsonian state. By examining the direction and strength of changes in effective connectivity at rest and during movement at different stages of PD we will be able to clarify the type, location and evolution of changes in effective connectivity as parkinsonian motor signs develop and progress in severity. A better understanding of the role of individual motor circuits and the types of physiological changes that occur within these circuits and how they relate to the development of individual motor signs will provide the rationale for the development of new targets, and technology therapies such as deep brain stimulation, transcranial electrical stimulation and gene therapy that are directed at restoring a more normal pattern of activity in the basal ganglia thalamic circuit.

DESCRIPTION (provided by applicant): This proposal addresses Challenge Area 15: Translational Science, and Specific Challenge Topic: Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease: 15-NS-103. Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by degeneration of dopaminergic neurons located within the substantia nigra, pars compacta (SNc). Chronic deep brain stimulation (DBS) in the subthalamic nucleus (STN) and the globus pallidus pars internus (GPi) has proven to be an effective therapy for the treatment of this disorder producing substantial improvements in tremor, bradykinesia, and rigidity, but has been less effective on improving gait and postural stability. Although there has been some recent exploration of the pedunculopontine nucleus (PPN) as a target for stimulation for the treatment of gait and balance problems in PD patients, the data are thus far extremely limited and highly controversial. The controversy stems in part from limitations associated with previous studies of PPN stimulation in non-human primates (NHP) as well as humans with PD. Few studies have systematically evaluated the effect of PPN stimulation on PD motor symptoms with confirmation of lead location within the PPN, either via postoperative imaging or postmortem studies in humans or histological confirmation in primate studies. Moreover, the primate studies performed to date have not quantitatively evaluated the effect of PPN stimulation on gait, while the data from human studies have been contradictory. These limitations make it difficult to determine whether the observed effect, or lack thereof, are indeed due to stimulation in the PPN. Although the PPN is considered a potentially effective target for the improvement of gait and balance in idiopathic PD, these limitations have led some to question its efficacy, while others rush to implant leads in patients before establishing physiological guidelines to identify the PPN and allow for accurate lead placement. To address these limitations we propose to: 1) characterize the electrophysiological features of neuronal activity in the PPN before and after MPTP administration in the parkinsonian primate model;and 2) implant and subsequently assess, using objective, quantitative measures, the effect of PPN DBS on gait in the MPTP NHP model of PD as the animal ambulates briskly on a treadmill. Histological confirmation of lead location will be performed following the assessments. The effect of PPN DBS on other motor signs of PD including bradykinesia/akinesia and rigidity will also be assessed in this study. We hypothesize that PPN neurons will exhibit a decreased mean discharge rate and increased bursting in the PD state secondary to increased inhibitory output from the internal segment of the globus pallidus (GPi) to the PPN. We also hypothesize that PPN DBS will be associated with a frequency dependent improvement in motor behavior, with low frequency stimulation patterns (i.e., 5 - 50 Hz) improving gait, akinesia and rigidity, while higher frequencies will exacerbate them. PUBLIC HEALTH RELEVANCE: This proposal addresses Challenge Area 15: Translational Science, and Specific Challenge Topic: Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease: 15-NS-103. The goal of this study is to determine whether electrical stimulation of certain brain regions can be used to improve the gait and balance instabilities associated with Parkinson's disease (PD). An animal model of PD will be used to study the effect of deep brain stimulation (DBS) of the brainstem pedunculopontine nucleus (PPN) on gait dysfunction. The PPN is considered a potentially effective target for the improvement of gait and balance in PD by a number of preliminary studies. However, these studies have several limitations, leading some to question its efficacy, while others rush to stimulate PPN in patients before sufficient guidelines are established for accurate localization of this target. To addresses these limitations, this study will characterize the changes in neuronal activity that take place in the PPN following development of PD, help determine physiological guidelines that can be used to identify the PPN for lead placement, and quantitatively characterize the effect of PPN DBS on PD motor symptoms. This study will determine whether or not PPN DBS can be effective in treating these motor signs and provide a rationale-based approach to the development of future clinical trials of PPN DBS for the treatment of PD symptoms. As a treatment of gait dysfunction, the utility of PPN DBS may extend beyond the PD population to other movement disorders, including progressive supranuclear palsy and multiple systems atrophy.

The overall aim of this project is to clarify the relationship between neuronal activity in the internal segment of the globus pallidus (GPi) and the development, phenotypic distribution and severity of dystonic movements in patients with primary generalized (PGD) and cervical dystonia (CD). Three fundamental questions will be addressed: 1) What are the physiological characteristics of neurons in the basal ganglia in patients with PGD and CD? 2) Is there a relationship between those physiological characteristics ( e.g. mean discharge rate, somatosensory response properties, or the number of cells with bursting or power at low oscillatory frequencies) and clinical measures of dystonia severity (Burke Fahn Marsden Dystonia Rating Scale for PGD and Toronto Western Spasmodic Torticollis Rating Scale for CD)? and 3) Is there a difference in the relative proportion and distribution of neurons in the GPi that demonstrate these dystonic characteristics between patients with PGD and those with CD? Neural and force control data will be gathered simultaneously in the operating room during microelectrode mapping of the GPi as part of deep brain stimulation surgery. As part of this two-year project, neuronal, EMG and force control data will be collected from 18 (9 PGD and 9 CD) dystonia patients. Specific Aims 1 and 2 are focused on determining the relationship between neuronal activity (i.e. mean discharge rate, pattern, oscillatory activity and somatosensory response properties) within the GPi and the severity of PGD and CD, respectively. The final phase of Aims 1 and 2 will be to compare the neural activity within the GPi in patients with PGD and CD. This comparison will allow us to determine if PGD and CD patients have common alterations in neural activity or if each type of dystonia has its own unique'pathophysiology. In Specific Aim 3, patients will perform a force-tracking motor task during the recording of neural activity within GPi. Motor performance will be objectively quantified using biomechanical measures. The simultaneous collection of neural and motor data is unique and will clarify the relationship between neuronal activity within the GPi of PGD and CD patients and their specific impairments in the control of muscle forces, in particular the scaling and focusing of force. Identifying specific physiological characteristics associated with dystonia, determining the spatial segregation of affected neurons in PGD and CD and understanding the specific motor impairments of each will refine current surgical strategies and may lead to new surgical approaches to relieve dystonic symptoms.

This Integrative Graduate Education and Research Traineeship (IGERT) award supports the development of a multi-disciplinary, integrative graduate education and training program in NeuroEngineering (NE) at the University of Minnesota at Twin Cities. Intellectual Merit: The purpose of this program is to train doctoral students to develop the skills to revolutionize technologies for interfacing with the brain and advance the fundamental understanding of neuroscience processes that arise when interfacing with and modulating the brain.

Broader impacts include the development of a multi-disciplinary training program that blurs the boundary between neuroscientists and engineers, thus enabling a new generation of scientists to competently and confidently take on the grand challenges in the interdisciplinary field of NeuroEngineering. The NE program includes major research themes in decoding brain signals, modulating brain dynamics, and bi-directional brain interfacing. The program is a "degree-plus" model in which pre-doctoral students are admitted to one of the participating graduate programs (Biomedical Engineering, Electrical Engineering, Mechanical Engineering, and Neuroscience), and are trained through a series of hands-on, modular neuroengineering courses. All NE Fellows will immerse themselves in a lab outside their major in the summer of their first year, engage in multiple lab rotations, and participate in at least one clinical lab rotation, summer internship at a neurotechnology company, or summer international research experience. NE Fellows will have co-advisors beginning in their first year, one from the engineering sciences and one from the basic or clinical neurosciences. The training program incorporates several outreach efforts to recruit women and underrepresented minorities, provide outreach to K-12 and industry, and train NE Fellows to be effective communicators.

IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.

DESCRIPTION (provided by applicant): The motor cortex (MC) and supplementary motor area (SMA) are components of a subcortical-cortical and cortical-cortical network intimately involved in motor control, in mediation of the development of motor signs in Parkinson's disease (PD), and the improvement in motor function during deep brain stimulation (DBS). Yet, the role of these cortical motor areas in the development of motor signs and pathophysiology of PD remains ill-defined. Similarly, the effects of DBS in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) on neuronal activity in the MC and SMA are largely unknown. To date, there are only a few studies in parkinsonian animals that have examined neuronal activity changes in the MC and SMA and fewer still that have performed these studies during DBS in the STN or GPi. The current proposal will characterize these changes in the MPTP monkey model of PD and those neuronal activity changes that occur in the MC and SMA during DBS (STN and GPi) both at rest and during passive and active movement. We will determine if specific neuronal activity changes correlate with improvements in motor symptoms detected during DBS. In addition, we will use chronically implanted microarrays to assess the changes in cortical activity on each side of the brain during chronic unilateral stimulation correlating them to coincident changes in motor signs on both the ipsilateral and contralateral sides of the animal. This study will provide new insights into the pathophysiology of PD, provide a greater understanding of the cortical mechanisms underlying the improvement in motor symptoms during DBS and investigate the cortical mechanisms that underlie improvement in ipsilateral motor signs during unilateral stimulation. Results from this study will allow us to beter determine which neuronal patterns of cortical activity correspond to the development of, and improvement in, motor signs and provide specific rationale for designing programming algorithms directed at modifying cortical activity to optimize clinical outcomes in PD patients treated with DBS and form the basis upon which closed loop programming methods could be developed. PUBLIC HEALTH RELEVANCE: Millions of people in the U.S. and worldwide have been diagnosed with Parkinson's disease, a progressively debilitating disorder characterized by abnormal movement function. Fortunately, many patients with advanced disease who no longer respond adequately to medications have been successfully treated with an FDA- approved implantable device that provides electrical stimulation deep within the brain, a therapy known as deep brain stimulation (DBS). While DBS may significantly reduce symptoms in many cases, there is still much that is unknown about the way it works, especially under different conditions. Our goal is to obtain a better understanding of how DBS works in and between specific regions of the brain to improve movement function and to apply this knowledge to optimize DBS therapy for patients affected by movement disorders, such as Parkinson's disease. In this study, we will use non-human primates with Parkinson-like symptoms to examine the effects of chronic stimulation in two specific areas of the brain that are known to improve symptoms in both affected non-human primates and patients. Stimulation in these areas causes activity changes in and between cortical regions of the brain involved in planning and executing physical movement. A longitudinal study of the changes in cortical activity in relation to changes in the rate and quality of specific movements under different stimulation conditions and locations will provide a basis upon which new DBS therapies may be developed or improved.

PROJECT SUMMARY/ABSTRACT The pathophysiological basis underlying the development of parkinsonian motor signs (PMS) and how deep brain stimulation (DBS) works to improve them is unclear. Synchronized oscillations in the beta band have been proposed to play a significant role, but how this activity leads to the development of the motor abnormalities in Parkinson's disease (PD), the potential role of oscillatory activity in other frequency bands and how this affects neuronal activity in the basal ganglia thalamo-cortical circuit (BGTC) are not well understood. In this proposal we will further explore the cortical-subcortical interactions that underlie the development of PMS, how DBS modifies this activity, and compare DBS to L-dopa alone or with DBS by examining the changes in synchronized oscillatory activity, coupling and connectivity changes that occur between cortical and subcortical structures under these different conditions. To better understand the relative effect of stimulation focused into motor versus nonmotor regions of the subthalamic nucleus and internal segment of the globus pallidus on BGTC circuitry and motor signs we will compare the effect of DBS directed into motor versus nonmotor regions using segmented lead technology, explore whether these interactions change with continued DBS and develop novel algorithms for closed loop DBS that include both beta and gamma frequency spectrums and incorporate a novel ?phasic stimulation? approach where stimulation is timed to a specific phase of the oscillation. The nonhuman primate MPTP model of PD will be used and animals will be assessed both at rest, as well as during passive movement and task related activity. This study will provide a greater understanding of the pathophysiological changes that occur in BGTC circuitry in PD, further delineate the mechanisms underlying the therapeutic effects of DBS and L-dopa, and characterize the effect of directional DBS on BGTC circuitry and motor signs, while identifying physiological biomarkers to be used for closed loop algorithms that improve motor signs both at rest and during task related activity where biomarker activity is dynamic and constantly changing.

ABSTRACT The University of Minnesota Udall Administrative Core, led by the Center Director Jerrold Vitek, MD, PhD, assisted by the Center Administrator Anthony Santiago, MD, will provide leadership, oversight, and coordination of all Projects and Cores, including: integration of all Projects and Cores; production of the annual progress report; timely communication of research discoveries, publications, funding sources; all cross-training and career enhancement programs; the pilot grant program; local PD community outreach efforts; and, the annual local patient symposium. The goals and planned activities of the Center Administrative team will provide an organizational foundation for research activities, and serve its mission as a local, regional and national resource for Parkinson's disease (PD) research and patient care.

ABSTRACT  The overall goal of project 1 of the University of Minnesota (UMN) Udall Center is to characterize the pathophysiological basis underlying the development of parkinsonian motor signs and use this information to refine current and develop alternative deep brain stimulation (DBS) strategies for the treatment of Parkinson?s disease (PD). Parkinson?s disease is a devastating neurodegenerative disease, yet we understand little about the pathophysiological changes that underlie the abnormal movements associated with this disorder. Although deep brain stimulation (DBS) has been demonstrated to reduce motor signs and improve the quality of life for patients with PD, outcomes vary significantly among patients and for individual motor signs within patients. This project will examine the relationship between changes in synchronized neural activity and motor behavior directly in patients by leveraging opportunities afforded by intra-operative, microelectrode mapping of the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) during DBS surgical procedures as well as post-operatively in patients with temporarily externalized DBS leads and using the fully- implanted Medtronic Activa© RC+S ?Brain Radio? system. The specific aims of this project are to: (1) identify the changes in oscillatory brain activity that are associated with abnormal movements through intraoperative recordings of neuronal (single and paired) and LFP activity during the performance of reaching and repetitive movement tasks; (2) further characterize the changes in that oscillatory activity in response to pharmacological and DBS treatment that reduces motor signs; (3) evaluate the potential role of these oscillatory changes as pathophysiological biomarkers for use in adaptive, closed-loop DBS systems; and (4) evaluate the acute and carry-over effects of coordinated reset (CR) DBS of the STN on both motor signs and oscillatory activity using the Activa© RC+S implant. The RC+S implant allows for subcortical local field potential (LFP) recordings and novel stimulation paradigms to be administered post-operatively, in the fully implanted patient, thus providing a unique opportunity to postoperatively evaluate the potential role of synchronized oscillatory activity in specific frequency spectrums as therapeutic biomarkers in next-generation DBS systems. The simultaneous collection of neuronal and LFP data during motor behavior intra-operatively is unique and will clarify the role of changes in neural activity, including synchronized oscillatory activity within and across specific frequency spectrums within the GPi, GPe and STN with abnormalities in motor performance. Overall this project will enhance our understanding of the pathophysiological basis of PD motor signs, clarify the changes in oscillatory activity that occur within the pallidum and STN during movement and how they change in response to interventions that improve motor signs. This study will also provide the rationale for the development of closed-loop and novel DBS paradigms designed to induce long term improvements even after discontinuation of stimulation.    

The University of Minnesota (UMN) Udall Center will focus on understanding the electrophysiological features that underlie the motor signs of Parkinson's disease (PD) and developing new deep brain stimulation (DBS) strategies to treat them. This will be accomplished in humans through a combination of intra-operative microelectrode and post-operative local field potential (LFP) recordings using the Medtronic RC+S ?Brain Radio?, and DBS therapy implemented through the lens of novel targets and stimulation paradigms. These data will be complemented in nonhuman primates, by the development and electrophysiological characterization of optimization tools for improving subject-specific precision of DBS therapy. Specifically, the first goal (Project 1) is to enhance our understanding of the pathophysiological basis of PD motor signs by clarifying the changes in synchronized oscillatory activity that occur within the pallidum and STN at rest and during movement under conditions that improve and worsen motor signs (during DBS or following administration of levo-dopa). These data will provide the rationale for the development of novel DBS paradigms and targets. The second goal (Project 2) is to identify the physiological signatures associated with dopa-responsive and resistant motor features of PD, use MRI-derived computational models to examine the pathways mediating the behavioral changes and investigate alternative DBS targets and stimulation paradigms to treat these motor signs. The third goal (Project 3) is to leverage the well-established MPTP nonhuman primate model of PD to identify unconventional DBS settings that increase the window between successful therapy and emergence of side effects, develop closed-loop strategies for tuning DBS settings to maximize the therapeutic effect on individual parkinsonian motor signs, and investigate how the level of therapy depends on electrophysiological changes in the basal ganglia, thalamus, and brainstem. Critical to all three projects is the ability to accurately determine DBS lead and contact locations, and develop model based predictions of which motor pathways are activated during stimulation (Imaging Core). Clinical and quantitative motor assessments will be obtained (Clinical Core) and correlated to physiological data obtained acutely in the operating room, subacutely in patients whose leads are externalized and chronically through postoperative assessments using the Medtronic RC+S ?Brain Radio?. The Biostatistics Core will provide study design, logistics planning, overall data management, quality control and statistical analysis, as well as data integration with and transfer to the NIH/NINDS Data Management Resource. The Administrative Core will support all aspects of the UMN Udall Center, implement and support patient education and public outreach efforts and provide training for the next generation of PD researchers. Together, these approaches will provide critical data towards the development and translation of novel patient-specific DBS therapies.