Thomas Wichmann - US grants

DESCRIPTION: (Verbatim from the Applicant's Abstract) The basal ganglia are part of larger circuit that involves thalamus and cortex. Cortical inputs reach striatum and subthalamic nucleus (STN), and are transmitted via internal pallidal segment (GPi) and substantia nigra pars reticulata (SNr) to influence the activity of thalamocortical neurons. The function of this circuitry is disturbed in Parkinson's disease because of loss of dopamine in the basal ganglia. Besides changes in discharge rates, basal ganglia neurons also develop significant abnormalities in their discharge patterns in parkinsonism. One of the most salient abnormalities is the appearance of synchronized oscillatory discharge in STN, the external pallidum (GPe), GPi/SNr, and frontal cortex (detected by EEG). Available data suggest that this may result from altered activity along the cortex-STN-GPi/SNrthalamocortical route. With a combination of extracellular basal ganglia recordings and EEG, the proposed primate experiments explore the relationship between oscillatory activity in cortex and basal ganglia and will test the hypothesis that oscillatory discharge in the cortex-basal ganglia circuitry contributes to parkinsonism. The correlation studies under specific aim (S.A.) 1 assess the link between neuronal discharge in the basal ganglia (GPe, STN GPi, SNr) and EEG with simultaneous recordings in both brain regions. The importance of striatal or extrastriatal dopamine loss for the development of oscillatory discharge in parkinsonism will be tested under S.A. 2 by studying changes in oscillatory activity in basal ganglia and cortex induced by microinjections of the dopamine receptor agonist apomorphine at striatal and extrastriatal basal ganglia sites in parkinsonian animals. The experiments under S.A. 3 will test whether blockade of glutamate receptors in STN (blocking corticosubthalamic inputs) reduces oscillatory activity in basal ganglia and cortex. Finally (S.A. 4), the hypothesis will be tested that synchronized oscillatory discharge in the basal ganglia, induced by electrical stimulation of STN with bursts of stimulation pulses at burst rates between 2 and 30 Hz, disrupts motor performance and induces parkinsonian motor abnormalities in normal monkeys. These studies will help to understand the significance of oscillatory discharge in the basal ganglia and cortex in parkinsonism. This may provide guidance in the development of drug treatments directed at normalizing abnormal discharge patterns, and may help to understand the mechanism of action of existing treatments for Parkinson's disease, including dopamine receptor agonists, glutamate receptor antagonists, and deep brain stimulators.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cortical inputs reach basal ganglia structures, which project back to thalamus and cortex. Due to the lack of the neurotransmitter dopamine synchronized oscillatory and non-oscillatory activity appears in the basal ganglia which can be measured with local field potential (LFP) recordings. In our primate experiments, we study recordings of LFP changes that are associated with the induction of parkinsonism by treatment with the neurotoxin MPTP. We also studied the local effects of dopaminergic drugs on neuronal synchrony in the basal ganglia nuclei, using a microdialysis/LFP recording probe which allows us to assess the effects of drugs, applied locally via reverse microdialysis, on LFPs in the vicinity of the probe. In this funding period we focused on studies of LFP abnormalities in parkinsonian animals. The studies are carried out in an animal that is undergoing a very slow course of MPTP treatment, combined with careful monitoring of the parkinsonian phenotype. Another animal (the third in this series) is currently being prepared for MPTP treatment. In the last funcitn period we also completed our series of studies of LFP changes produced through blockade of receptors for the inhibitory neurotransmitter GABA in the striatum, and their modulation through the local application of dopamine receptor blockers. GABA receptor blockade induced recurrent large LFP events which were not directly synchronized to neuronal activity in the immediate vicinity of the LFP probe, therefore likely reflecting synchronous synaptic inputs instead. In addition, the study resulted in the creation of a new video analysis method to track wakefulness through observations of eye lid opening.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for patients with Parkinson's disease, but the effects of this treatment on brain activity remain unknown. We therefore study the electrophysiologic and biochemical effects of DBS in normal and parkinsonian monkeys. Parkinsonism is induced by treatment with the dopaminergic neurotoxin MPTP. In the past funding period, we continued to study effects of STN stimulation in two normal animals. We found that STN stimulation produced effects on the activity of basal ganglia neurons that were more varied than previously appreciated. Although the effects of STN stimulation would be expected to be excitatory, firing rate changes in neurons that receive STN input varied substantially, ranging from inhibition to strong excitation. In many neurons the effects of short- and long-term stimulation differed, indicating the presence of adaptive changes. We also undertook a detailed analysis of firing pattern changes associated with STN stimulation. The stimulation-associated firing patterns differed between short- and long-term stimulation. We are currently completing microdialysis studies of the effects of STN stimulation on local levels of the inhibitory neurotransmitter GABA. We also repeated the same studies in two additional animals which were MPTP-treated. These experiments have been completed, but the results have not been analyzed. This part of the studies is crucial for a better understanding of the effects of electrical stimulation on basal ganglia activity in parkinsonian individuals. Insights into the mechanism of action of DBS in parkinsonism are needed to devise better stimulation protocols, may help to optimize placement of the stimulation probes in parkinsonian patients, and may help us to formulate rational pharmacologic approaches to maximize the beneficial effects of DBS and minimize its side effects.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. These studies examine the functional interactions and the anatomy of the connections between the intralaminar nuclei of the thalamus (i.e., the centromedian and parafascicular nuclei (CM/PF)) and the striatum in normal and parkinsonian monkeys. CM and PF send a topographically organized projection to the striatum. Movement-related projections from the CM terminate in the putamen which may act to shape striatal output under normal and pathologic conditions. The CM/PF complex is empirically targeted for neurosurgical interventions, such as deep brain stimulation (DBS), in the treatment of patients with Tourette's syndrome and Parkinson's disease. We have found that electrical CM stimulation with short trains of stimuli results in complex sequences of activation and inhibition in striatal cells, which are most easily explained as the result of intrastriatal spread of activity and processing within the striatal circuitry, for instance through local inhibitory axon collaterals and cholinergic interneurons. The ongoing studies (started earlier this year) contrast striatal responses to CM/PF stimulation in normal and parkinsonian monkeys with a combination of electrophysiologic recordings, microinjections, and anatomic studies. In this funding period, we have started to reconstruct the anatomical inputs from CM to specific dendritic domains of cholinergic striatal interneurons (one of the major striatal recipients of CM inputs). In addition, we are studying CM inputs to chemically defined subtypes of striatal output neurons. Finally, we have started electrophysiological recordings in one animal to study the effects of electrical stimulation of the CM on the activity of cholinergic neurons in the striatum. The proposed studies will provide us with information regarding the anatomy and physiology of the thalamostriatal system, and its involvement in parkinsonism, will clarify the effects of electrical stimulation of CM, and will provide data to help clinicians optimize parameters for CM-DBS therapy in parkinsonian patients.

Neurosurgical interventions, such as deep brain stimulation (DBS) of the internal pallidal segment (GPi) or the subthalamic nucleus (STN), or GPi lesions (pallidotomy), are commonly used to help patients with advanced Parkinson's disease. DBS and lesioning procedures produce contrasting effects on their immediate brain targets: Lesions reduce the output of the lesioned nucleus, while electrical stimulation of STN or GPi is thought to lead to complex activity changes in the stimulated tissue, including local neuron inhibition, and stimulation of efferent or afferent fibers. Despite these differences, lesions and stimulation have remarkably similar clinical and behavioral effects. We hypothesize that one of the reasons for this paradox is that, although the surgical interventions produce different local effects, they lead to similar effects in nuclei further downstream, particularly in the anterior ventrolateral thalamus (VLa), the recipient of a dense GABAergic projection from the motor portion of the basal ganglia output nuclei. Previous studies have suggested that VLa neurons show an increased tendency to fire in bursts and to generate oscillatory patterns of activity in parkinsonism, which may act to disrupt thalamocortical interactions, and may be involved in the generation of parkinsonian signs. We hypothesize that lesions and DBS aimed at GPi or STN have different effects on VLa firing rates, but that both regularize the firing patterns of VLa neurons, thus allowing cortico-thalamo-cortical interactions to proceed more normally. To test these hypotheses, we will examine the effects of GPi inactivation on neuronal activities, GABA levels, and morphological aspects of the synaptic pallldothalamic interactions in MPTP-treated (parkinsonian) monkeys (aim 1). Results from these studies will then be compared with the effects of electrical stimulation of STN or GPi on thalamic neuronal activity in MPTP-treated monkeys (aim 2). A better understanding of the common downstream effects of lesions and stimulation may help us to define more specific neurosurgical or pharmacological therapies, or therapies that combine pharmacologic treatments with the neurosurgical interventions, in order to eliminate parkinsonisian motor signs.

DESCRIPTION (provided by applicant): The Morris K. Udall Parkinson's Disease Center of Excellence at Emory University will be a highly collaborative research program in which electrophysiologists, pharmacologists, and anatomists work together to study the effects of existing and new treatments for parkinsonism from a circuit perspective. The Center draws upon the proven ability of the basal ganglia research community at Emory to conduct translational research. Other Center assets will be its close ties to the clinical movement disorders group at Emory, the fact that a portion of the research will be carried out in primates at the Yerkes National Primate Research Center, and the Center's connection to an active population of patients with Parkinson's disease in the Atlanta area. Emory University is strongly committed to Parkinson's Disease research, and will support the Center by funding pilot grants and an invited speaker seminar series. The center will consist of four projects and two cores. Project 1 (Dr. Jaeger) will examine changes imposed by altered basal ganglia input onto thalamic neurons in the parkinsonian state. Project 2 (Dr. Wichmann) is a series of experiments in parkinsonian primates to compare the thalamic effects of pallidal and subthalamic nucleus inactivation and stimulation, as are commonly used to treat advanced parkinsonism in patients, with the goal of identifying changes in thalamic activity that are associated with the antiparkinsonian effects of these procedures. Project 3 (Dr. Miller) is a series of translational experiments that examine the use of orally active TrkB receptor agonists as symptomatic or neurorestorative treatment for Parkinson's disease in different rodent and primate models. Project 4 (Dr. Conn, Vanderbilt), investigates the effects of a series of novel subtype-selective muscarinic acetylcholine receptor antagonists and activators on basal ganglia activity, and on parkinsonism in rodent models. The projects will be supported by an administrative core (Core A, Dr. Wichmann, PI;Dr. DeLong, Co-1, Dr. Pearson, administrator), and by an anatomy and behavior core (Core B, Dr. Smith) which will provide immunohistochemistry and electron microscopy services to all of the center projects, and will conduct behavioral testing in MPTP-treated monkeys under project 3. PUBLIC HEALTH RELEVANCE: The Center will foster collaborative Parkinson's disease research, train young investigators, and educate the public about the disease. The Center's research will take a circuit level approach to explore synaptic and circuit interactions in the basal ganglia-thalamo-cortical network. It will increase our understanding of how existing therapies work, and develop and explore the mechanisms of action of new antiparkinsonian treatments. PROJECT 1 Principal Investigator: Dieter Jaeger, PhD Title: The Role of Mouse Motor Thalamus Relaying Basal Ganglia Outflow Description (provided by applicant): We will examine how the motor thalamus in mouse models of Parkinson's disease (PD) Is Involved In transmitting Parkinsonian activity patterns generated In the basal ganglia to the cerebral cortex. We will use simultaneous electrophysiological recordings from basal ganglia, thalamus, and cortex In anesthetized and awake mice to determine the presence of pathological activity patterns, and their relations between structures. One strength of the proposal consists of the use of in vivo intracellular thalamic recordings, which will allow us to examine the hypothesis that strong basal ganglia bursting activity observed In PD will trigger post inhibitory rebound bursting In thalamus. Previous work suggests that such bursting in the basal ganglia Is one of the characteristics of pathological activity patterns in PD, but the transmission of this activity through thalamus to cortex remains unclear. We will carry out a detailed analysis of the specific mechanisms of synaptic integration in motor thalamus of the mouse In the brain slice preparation, where we test the control of action potential initiation by Parkinsonian patterns of Input. Finally, we will determine whether pharmacological compounds known to Interact with thalamic cellular properties (M1 and M4 muscarinic receptor agonists or antagonists or selective Cav3 calcium channel blockers) can be used to reduce the transmission of pathological activity from the basal ganglia through thalamus to cortex. This project is tightly Integrated with the other projects of the overall Emory Udall Center grant application: We share the focus on thalamic processing with project 2, where it will be examined In primates rendered Parkinsonian with MPTP. We share the VMAT2L0 mouse model of PD with project 3, where it will be used to determine possible neuroprotective treatment strategies. Our analysis of pathological electrical activity patterns In the VMAT2L0 mouse developed by Dr. Miller at Emory will aid in the validation of this model. We obtain the pharmacological compounds to be tested for specific effect on thalamic processing through our interactions with project 4. These compounds mentioned above are promising novel specific receptor agonists and antagonists as well as channel blockers that are not otherwise available Public Health Relevance: The public health relevance of this project is the study of novel treatments for Parkinson's disease that target the motor thalamus. In addition, the expected results will help us to better understand how much transgenic mouse models of Parkinson's disease repeat the same pathological activity patterns in the brain as seen in human patients, and to determine which mouse model can be best used for detailed treatment studies.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The recently funded Morris K. Udall Parkinson's Disease Center of Excellence at Emory University is a highly collaborative research program in which electrophysiologists, pharmacologists, and anatomists work together to study the effects of existing and new treatments for parkinsonism from a circuit perspective. The center consists of four projects and two cores. Project 1 (Dr. Jaeger) examines changes imposed by altered basal ganglia input onto thalamic neurons in the parkinsonian state. Project 2 (Dr. Wichmann) is a series of experiments in parkinsonian primates to compare the thalamic effects of pallidal and subthalamic nucleus inactivation and stimulation, as are commonly used to treat advanced parkinsonism in patients, with the goal of identifying changes in thalamic activity that are associated with the antiparkinsonian effects of these procedures. Project 3 (Dr. Miller) is a series of translational experiments that examine the use of orally active TrkB receptor agonists as symptomatic or neurorestorative treatment for Parkinson's disease in different rodent and primate models. Project 4 (Dr. Conn, Vanderbilt) investigates the effects of novel subtype-selective muscarinic acetylcholine receptor antagonists and activators on basal ganglia activity, and on parkinsonism in rodent models. The projects are supported by an administrative core (Core A, Dr. Wichmann, PI;Dr. DeLong, Co-I, Dr. Pearson, administrator), and by an anatomy and behavior core (Core B, Dr. Smith) which provides immunohistochemistry and electron microscopy services to all of the center projects, and conducts behavioral testing in MPTP-treated monkeys under project 3.

DESCRIPTION (provided by applicant): The motor dysfunction of Parkinson's disease is usually described as the result of changes in the activity of basal ganglia-thalamocortical circuits. However, recent research has shown that the heterogeneous family of thalamostriatal projections may also be strongly affected by the disease, and that these changes may contribute to the development of parkinsonian signs and symptoms. The most substantial thalamostriatal projection comes from the caudal intralaminar nuclei in the thalamus (the centromedian and parafascicular nuclei [CM/Pf]). The CM/Pf-striatal projection gives rise to clusters of axon terminals that target preferentially dendritic shafts of striatal projection neuros, as well as cholinergic interneurons. This projection may be prominently involved in the processing of reward information and in the regulation of vigilance and attention. Another major source of thalamostriatal fibers are the 'basal ganglia receiving' ventral anterior (VA) and ventrolateral (VL) nuclei. Neurons in these nuclei send long un-branched axons to the striatum, with many en passant-type varicosities. The impact of the VL-striatal projections on striatal function is unknown. Postmortem analysis of brain tissue from parkinsonian patients has demonstrated that the source nuclei of the thalamostriatal projection and the organization of their synapses in the striatum are strongly affected by the neurodegenerative process. Neurons in the CM/Pf are particularly affected, with degeneration of more than 50% of neurons early in the course of the disease. We have demonstrated that these aspects of neuron loss are faithfully replicated in MPTP-treated (parkinsonian) monkeys, along with a corresponding decrease in thalamostriatal terminals. In addition, there are extensive changes in the morphology and density of dendritic spines in the striatum, which are the primary recipients of VL input. The functional impact of these changes on striatal activity is not known, but is likely t be substantial, and, given the anatomical and pathological differences, may differ between the two projection systems. We propose to test this hypothesis with a combination of functional and anatomical studies in monkeys. The functional studies (aim 1) will make use of an optogenetic approach that will allow us to selectively activate terminals of the CM-striatal or VL-striatal projections, and to examine the resulting effects on the activity of striatal projection neurons an cholinergic interneurons in awake primates. These studies will first be done in the normal state, and then again after the animals have been rendered parkinsonian by treatment with MPTP. The functional studies will be complemented with quantitative electron microscopic analyses in the same animals, in which opsin expression will be used as an anatomic marker to identify parkinsonism-related changes in the postsynaptic targets of CM- or VL-striatal terminals (aim 2). The proposed studies will help us to gain a more complete understanding of the circuit pathophysiology of parkinsonism, and set the stage for the development of therapeutic strategies to treat Parkinson's disease through influencing specific thalamostriatal interactions.

Project Summary ? Project 2 It is not known how dopamine depletion in the basal ganglia in Parkinson's disease and the resultant abnormal activity in these structures, alter information processing in brain areas that are downstream from them, specifi- cally the basal ganglia receiving motor thalamus (BGMT). Information processing in the BGMT remains enig- matic. Unlike other areas of the thalamus, the BGMT receives no peripheral glutamatergic input and only weak glutamatergic `driver' input from the cerebral cortex. In addition, it is unique among thalamic nuclei because it is subject to massive inhibitory modulation from the basal ganglia. The BGMT projects to the primary motor cor- tex (M1), the supplementary motor area (SMA) and other cortical areas, but it is not known how these projec- tions influence cortical activities. As we and others have shown, information processing in thalamus and cortex are strongly altered by abnormal basal ganglia output in the parkinsonian state. There is also strong new evi- dence for synaptic (functional/morphologic) plasticity in the parkinsonian state that will further affect the activity of thalamic and cortical neurons (project 3). In the planned studies, we will assess how parkinsonism affects the processing of basal ganglia or cortical inputs to BGMT, and BGMT inputs to motor cortices. Under aim 1, we will use a combination of optogenetic and electrical stimulation methods to probe the impact of activating M1, SMA, or basal ganglia inputs on BGMT activity in normal and parkinsonian (MPTP-treated) monkeys. Based on preliminary findings, we expect to find that light activation of opsin-transfected corticothalamic termi- nals will lead to short-latency excitatory and long-latency inhibitory responses in BGMT, while (electrical) acti- vation of pallidothalamic fibers inhibits BGMT. We will also study interactions between these inputs. In aim 2, we will examine responses of cortical neurons to optogenetic activation of BGMT projections in normal and parkinsonian primates. We expect that the prominent and layer-specific parkinsonism-related plasticity at thalamocortical synapses (project 3) alters responses of cortical neurons to their BGMT inputs. We will particu- larly focus on cortical neurons with antidromic responses to electrical internal capsule stimulation, because the activity of these cells is known to be strongly altered in parkinsonian monkeys. Interactions with project 1 will provide important mechanistic information regarding parkinsonism-related changes in the excitability and spike patterning of thalamic and cortical neurons, while collaboration with project 3 will help us to incorporate mor- phological changes into our analysis. Core B will add essential anatomical results to our study, and will help us by generating parkinsonian animals. Taken together, the planned studies will help us to understand how pal- lidal and cortical inputs shape BGMT activity, how these effects influence M1/SMA activities, and how cortico- thalamic and thalamocortical transmission changes in parkinsonism. This knowledge may alter our view of the pathophysiology of parkinsonism, and will be essential for the rational development or optimization of surgical or pharmacological antiparkinsonian neuromodulation strategies that target basal ganglia or thalamus.  

The Morris K. Udall Parkinson's Disease Center of Excellence for Parkinson's Disease Research at Emory University is a collaborative research program in which electrophysiologists and anatomists study the pathophysiology of parkinsonism, and examine and optimize the effects of existing treatments for Parkinson's disease. The Center draws upon the proven ability of the basal ganglia research community at Emory to conduct translational research. Other Udall Center assets are its close ties to the clinical movement disorders group at Emory, and the availability of primates for research at the Yerkes National Primate Research Center at Emory University. Emory is strongly committed to the Udall Center's research, and supports the Center by funding pilot grants, invited speakers, and portions of its education and outreach programs. The Center consists of three tightly linked projects and two cores. The planned research will shed light on the poorly understood parkinsonism-related activity changes in thalamus and cortex which, in turn, will help us to better understand the pathophysiology of parkinsonism, and to optimize existing neuromodulation strategies and to develop new ones. Project 1 (led by Dr. Jaeger) will utilize brain slice and in vivo recordings in rodents, as well as a neural computational approach to develop mechanistic models of thalamocortical dysfunction in parkinsonism. Project 2 (Dr. Wichmann), will continue the exploration of thalamic and cortical abnormalities in parkinsonian monkeys, using selective activation and inactivation approaches which are designed to study corticothalamic, pallidothalamic and thalamocortical information transfer. Project 3 (Dr. Smith) will examine morphological changes in the thalamic and cortical microcircuitry in parkinsonian primates, a topic that is virtually unexplored at this time and of high relevance to the interpretation of data in the other projects. All projects will be supported by an Administrative Core (Dr. Wichmann, PI; Dr. DeLong, Co-I, Dr. Smith, Co-I, Ms Holbrook, administrator), and by an Anatomy and Behavior Core (Dr. Galvan) which will provide immunohistochemistry and electron microscopy services to all of the center projects, and standardized MPTP treatment and quantification of parkinsonism to the primate experiments in Projects 2 and 3. In addition to pursuing its research mission (Aim 1), the Center will help junior scientists to develop their career in Parkinson's disease research (Aim 2), and will engage in extensive outreach efforts, aimed at communicating the Center's (and Udall Center network) research findings to the public (Aim 3), reaching all age groups and background levels, ranging from K-12 children to retirees in assisted living facilities. As part of the outreach agenda, the center plans to organize annual symposia for patients and their caregivers. The center will be generously supported by the University. These internal support funds will help the Center to fund some of its education and outreach missions, as well as its pilot grant program, designed to expand Parkinson's disease research at Emory University.

ABSTRACT In current schemes of the pathophysiology of Parkinson?s disease (PD), neuronal activity changes in the sen- sorimotor region of the subthalamic nucleus (STN) play a central role in the development of parkinsonism. Until recently, the changes in STN activity were thought to result solely from reduced inhibition from the external globus pallidus (GPe). However, recent findings from animal models of advanced parkinsonism have suggested that a profound loss of glutamatergic cortico-subthalamic terminals and an increased strength of GABAergic pallidosubthalamic synapses may contribute to activity changes in the STN and to the development of parkin- sonism. Our preliminary data demonstrate that a loss of cortico-subthalamic terminals is also present in the sensorimotor STN territory of people with advanced PD. It remains unclear, however, how these anatomical and physiologic changes relate to the degree of nigrostriatal dopamine loss and to the expression of parkinsonism. Further, it is unknown if these changes also affect non-motor regions of the STN, perhaps contributing to cogni- tive or affective PD symptoms. We will examine these issues with neuropathological and electrophysiological studies in monkeys with different degrees of MPTP-induced dopamine loss (Aim 1), and with longitudinal 7T ultra-high field MRI studies in people with early PD (Aim 2). In Aim 1, we will record responses of STN neurons to optogenetic activation of cortical and pallidal inputs in monkeys that remained either asymptomatic after ex- posure to small dose of the dopamine-depleting neurotoxin MPTP or became parkinsonian after exposure to (larger doses of) MPTP. We will also assess changes in local field potentials (LFPs) and abnormal spiking activity in STN, and in the coherence between STN LFPs and motor cortical electrocorticograms. In postmortem studies of the same animals, we will use high resolution microscopic immunohistochemical studies and 3D-EM reconstructions to assess whether the number, localization, and morphology of glutamatergic and GABAergic synapses in the STN changes as a function of dopamine loss. We will also compare the number of cortico- subthalamic terminals and examine changes in GABAergic markers in STN tissue from patients with PD and age-matched controls. In Aim 2, we will use state-of-the-art diffusion and resting state functional MRI to test whether humans with early stage PD exhibit significant changes in the volume and microstructural organization of the STN and its cortical and pallidal afferents, and determine if these changes are related to the expression and progression of motor and non-motor impairments. The same patients will be studied at enrollment and 30 months later to examine changes in the MRI measures. The results of this project will increase our understanding of the temporal evolution of parkinsonism-associated plastic changes in the STN, and determine their potential relationships to the development and severity of motor and non-motor signs and symptoms of the disease. These studies may lead to novel interventions to control or prevent abnormal firing patterns in STN and may contribute to the development of imaging biomarkers to identify early stages of PD and predictors of disease progression.

Project Summary ? Overall Center The Morris K. Udall Parkinson's Disease Center of Excellence for Parkinson?s Disease Research at Emory University is a collaborative research program that studies the pathophysiology of parkinsonism with the goal of optimizing the treatment for Parkinson?s disease (PD). The Center draws upon the proven ability of the basal ganglia research community at Emory to conduct collaborative translational research. Other Udall Center assets are the availability of primates for research at the Yerkes National Primate Research Center at Emory, and the presence of one of the largest movement disorders clinic in the US. The Center consists of four projects and three cores. The planned research will shed light on the poorly understood parkinsonism-related activity changes of specifically identified groups of projection neurons in the cerebral cortex which, in turn, will help us to better understand the pathophysiology of parkinsonism, and to optimize therapeutic strategies. Project 1 (led by Dr. Jaeger) will utilize rodent experiments for large-scale voltage imaging and brain slice recordings and use neural computational approaches to develop mechanistic models of cortical dysfunction in parkinsonism. Project 2 (Dr. Galvan), will explore the spontaneous and task-related activity of corticostriatal and corticospinal neurons in the primary motor cortex (M1) and the supplementary motor area (SMA) in normal and parkinsonian monkeys, using an opto-tagging approach to identify the projection targets of the recorded neurons. Project 3 (Dr. Smith) will examine morphological changes in the M1 and SMA microcircuitry and parkinsonism-associated changes in the connectome of cortical projection neurons in primates, a topic that is virtually unexplored and of high relevance to the interpretation of data in projects 1 and 2. The clinical ?Catalyst? project 4 is an examination of parkinsonism-related changes in cortical activity in response inhibition tasks, studied in electrocorticography and electroencephalography signals in patients with PD. The functional experiments will also study the effects of levodopa and deep brain stimulation treatments in these paradigms. All projects will be supported by an administrative core (Core A, Dr. Wichmann, PI; Dr. Smith, Associate Director, Ms Holbrook, administrator), and by a service core that provides anatomical services to projects 1 and 2, behavioral assessments to projects 2 and 3, and statistical services to all projects (Core B, Dr. Galvan). A clinical core (Core C) will support project 4 with recruitment and logistic services for the human studies. In addition to pursuing its research mission (aim 1), the Center will help young scientists to develop their career in PD research (aim 2), and will engage in extensive outreach efforts, aimed at communicating the Center?s (and Udall Center network) research findings to the public (aim 3), reaching all age groups and background levels. As part of the outreach agenda, the center plans to organize annual outreach events for patients and their caregivers. Generous internal support funds will help the Center to fund some of its education and outreach missions, as well as its pilot grant program, designed to expand PD research at Emory.