Noam Harel - US grants

Abstract Not Provided.

DESCRIPTION (provided by applicant): The immense impact of the fMRI technique on the neuroscience community, which allows noninvasive localization of active cortical regions, is well reflected by the exponential increase of publications utilizing this technique. For the past decade, great effort has been put into increasing the spatial resolution and specificity of fMRI signals from vessel-weighted to more tissue specific signals. The working assumption is that the "tissue" signals closely mirror changes at the neuronal level. While great progress has been made, the basic and most fundamental questions remain unanswered: Where in the tissue do these "tissue-fMRI" changes occur? Do they indeed originate at the site of the most active neurons/layer? The aim of this study is to identify the spatial and anatomical origin of the fMRI signals to the level of cortical layers. In this proposed study we will correlate high-resolution fMRI signals (0.15 x 0.15 mm2) with the underlying cortical laminar cytoarchitectonic and microvascular structures in the same animal and cortical section. In this proposal a new method for identifying and extracting the exact cortical tissue corresponding to the fMRI plane will be developed. Once extracted, the corresponding cortical slab will undergo standard histological staining procedures to uncover the laminar and vascular structures. Thus, based on histological criteria obtained from the matching tissue, the spatial origin of tissue fMRI hemodynamic signals will be determined. The impact and outcome of this study will greatly enhance our understanding of the fMRI signal source. This in return will open the opportunity to study brain function and cerebral hemodynamic regulation at the laminar resolution, levels that are currently unattainable.

DESCRIPTION (provided by applicant): Correlation of Functional and Structural Units in Cerebral Cortex This proposal is an expansion of our earlier NIH R21 project that explored the spatial relationship between functional magnetic resonance imaging (fMRI) signals and the underlying neuronal architecture. In a combined high- resolution fMRI and histological study, conducted in the same animal and cortical region, we demonstrated for the first time that tissue fMRI signals peak at cortical layer IV. The spatial specificity of any hemodynamic-based mapping technique is bound by the underlying vascular network;therefore, the spatial relationship between the two is crucial for understanding the mechanisms governing and limiting these mapping techniques. The current understanding of the fMRI contrast mechanism, regarding its vascular origins, is based on numerous assumptions and theoretical modeling, but little experimental validation exists to support or challenge these models. Due to mainly technical limitations, the current knowledge of cerebral vasculature is limited to the large pial surface and capillary level vessels. However, little is known regarding the cluster of intermediate-sized, mainly the intracortical vessels, connecting these two groups and where, arguably, key blood flow regulation takes place. Building on our pervious findings, we will explore the spatial correspondence of fMRI signals with the underlying vascular organization. To accomplish the proposed goal several multimodal developments will be embarked on. A new method for in- vivo visualization and classification (veins and arteries) of cortical vessels will be developed. Utilizing a new and unique ultra high-field (16.4 T / 26 cm) magnet, a high-resolution MRI acquisition schemes combined with ex-vivo micro-CT imaging will enable detailed and accurate 3D modeling of cortical vasculature at resolution approaching the microscopic scale. In addition, analytical tools will be developed to provide morphological description and quantification of the vascular model. Capitalizing on this unique approach, the spatial distribution of stimulus-induced fMRI signal changes will be correlated with the underlying vascular model within the same animal and cortical region. Several hypotheses will be explored with respect to fMRI signals and the cortical vessel morphology such as vessels size and the spatial distributions throughout the tissue. Furthermore, by stimulating only subsets of the neuronal ensemble in primary visual cortex, 3D functional maps of ocular dominance and orientation columns will be generated and correlated with the vascular model. We will investigate whether these functional cortical assemblies are coupled to specific vascular units. The outcome of these studies will be twofold: initially, development of new and unique methodological tools that will provide ways for exploring vascular models. These techniques will be applied to a broad variety of applications that utilize knowledge of the vascular architecture;such application include, but not limited to, fMRI, cerebrovascular diseases, cancer angiogenesis research and models of cerebral thermal regulation all of which will greatly benefit from an accurate vascular model. In the second outcome, neurophysiology research and clinical applications will benefit;with better understanding of the vascular morphology and fMRI mechanism, one can expect the increase in spatial localization and spatial specificity of the fMRI signals to the site of neuronal activity. Clinical applications such as neurosurgery planning, epilepsy and brain tumor resections will all benefit from increased accuracy. Furthermore, if indeed a correlation between functional (neuronal) and structural (vascular) units exist, in the future, it may be used as a diagnostic tool for brain disorders prior to the appearance of any clinical behavioral symptoms. PUBLIC HEALTH RELEVANCE: Functional Magnetic Resonance Imaging (fMRI) is a technique that allows, noninvasively, the localization of active brain regions. Increased neuronal activity in the brain is followed by a small and localized increase in blood flow which can be measured using fMRI. While fMRI has revolutionized the field of human brain research, little is known about the underlying vascular origin of these hemodynamic-based signals. Using a powerful magnet, this study is aims to obtain extremely high-resolution images of cortical vessels, generate a 3-D model of the vascular tree and correlate it with the fMRI signals. The outcome of these studies will greatly enhance our understanding of the vascular network and benefit a variety of research applications including fMRI, cerebrovascular disease, and cancer angiogenesis.

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. The purpose of this study is to develop new imaging tools for direct visualization of small brain structures. Current clinical imaging methods do not have sufficient resolutions to resolve small brain nuclei that are the targets for DBS surgery. However, with recent advantages of MR technology, with stronger magnet (7T) and superior image resolution, it is feasible to image such structures.

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. Development of high-resolution diffusion tensor imaging (DTI) and diffusion spectrum imaging (DSI) capabilities in the non-human primate model. The aim of this study will be to 1) validate DTI/DSI fiber tracking algorithms by comparing to histological reconstructions of the fiber tracts. 2) To determine whether high-resolution diffusion-weighted images fiber tracking can image small fiber tracts within the basal ganglia circuits.

DESCRIPTION (provided by applicant): Subthalamic deep brain stimulation (DBS) is an effective for the treatment of Parkinson's disease (PD). However, little is known about the specific neural pathway(s) responsible for therapeutic benefit. Direct stimulation of either the hyperdirect pathway and/or the subthalamopallidal pathway represents two of the most likely candidates as the target. Therefore, the goal of this project is to combine patient-specific 7T imaging and neurostimulation models together to enable probabilistic identification of the stimulation pathways linked to changes in clinical outcome measures recorded from subthalamic DBS patients. This study will rely on tractography-activation models (TAMs) to guide clinical testing on a cohort of 30 subthalamic DBS patients. Our multi-disciplinary approach will integrate the latest advances in neuroimaging, neurostimulation modeling, and quantitative clinical outcome measures to customize DBS to these patients. The first aim will acquire high- resolution 7T MRI data prior to their implant surgery. These images will provide unparalleled anatomical characterization of each patient. The second aim will create patient-specific TAMs for each subject. These models will enable us to define theoretically optimal settings for focused activation of either the hyperdirect pathway or the subthalamopallidal pathway. The third aim will quantify the clinical outcomes achieved with stimulation parameters defined by either the TAM or traditional clinical practice. These clinical results will be coupled with the TAM predictions to create a probabilistic tractography-activation atlas (PTAA) for the subthalamic region. The results of this study will help identify optimal implantation locations for DBS electrodes, and enable theoretical prediction of stimulation parameter settings that focus activation on the targeted pathways and/or avoid side-effect pathways.

Abstract: The University of Minnesota (UMN) Udall Imaging Core, led by Noam Harel, Ph.D. and based at the University of Minnesota's internationally renowned Center for Magnetic Resonance Research (CMRR), will acquire state- of- the-art, high-resolution MRI for all subjects in Projects 1, 2 and 3. The overall goal of the Imaging Core is to use advanced imaging capabilities for direct visualization of anatomical targets for deep brain stimulation (DBS) surgery as well as provide the precise location of individual electrode contacts within the target following implantation. The Imaging Core will combine several cutting edge MRI techniques, including T1 and T2 weighted, susceptibility weighted imaging (SWI) and diffusion weighted imaging (DWI) for tractography to create patient- specific anatomical models of the target region and associated networks. For Projects 1 and 2, PD Parkinson's disease (PD) will be scanned on a 7 T MRI system using tools developed by our team at the CMRR. For Project 3, the non-human primates (NHPs) will be scanned on the newly installed, first of its kind, 10.5 T MRI scanner also at the CMRR. For each PD patient and each NHP, the Imaging Core will acquire high-resolution MRI data prior to implant surgery and a head CT scan after surgery. Images will be fused to provide a comprehensive anatomical model of the DBS target and the precise location of individual DBS contacts within each target. These images will provide unparalleled anatomical characterization specific to each individual. After post- processing analysis, the Imaging Core will create subject-specific computational models estimating the volume of tissue activated by DBS. Subject specific models of anatomical and functional connectivity developed by the Imaging Core will provide data that is vital for the completion of each project in the UMN Udall Center.

The aim of this proposal is to support the replacement of the world?s first 7 Tesla whole-body MR scanner with a Siemens 7 Tesla Terra system, a high-performance scanner with advanced RF capabilities yet capable of routine clinical operation. This replacement will greatly enhance ongoing NIH funded imaging research at the University of Minnesota, allowing investigators to fully utilize advanced neuroimaging capabilities developed at the Center for Magnetic Resonance Research (CMRR). This new system also provides the potential for clinical translational research, as the system was designed for routine clinical use, and the FDA?s approval for clinical neuro and extremity imaging is currently pending. The specific MR system requested is expected to be the first 7 Tesla MR system approved by the FDA for clinical use in human subject. In anticipation of using this system both for biomedical research and clinically-billable scanning, we are requesting this as a Special Use Instrument, allotting up to 40% of its available time for clinical scanning. There are two primary aspects of the 7T Terra system that make this a compelling system for biomedical research. The first is that the system includes a 2nd generation, dynamic 8-channel parallel transmit capability that is built into the fundamental system design and is fully integrated into the system hardware and software. This system can produce completely independent waveforms for each of 8 channels, and integrates B1+ shimming, power calibration, and safety monitoring into the automated workflow. This will allow for the transfer of advanced parallel imaging techniques developed on the previous generation system to now be applied to any research application. The second feature of interest is that this system is explicitly designed for routine clinical use. Siemens has submitted a 510(k) application to enable the use of the Terra system for clinically reimbursable head and musculoskeletal imaging. While we are not dependent on this approval for our own research activities, using a system designed for routine clinical use gives much greater stability and consistency than prototype research systems.

PROJECT SUMMARY AND ABSTRACT Essential tremor (ET) is the most common movement disorder in the United States, affecting 4% of all adults over the age of 40. For individuals whose motor symptoms are refractory to medication and significantly impair their daily living, deep brain stimulation (DBS) is considered to be the only bilateral therapeutic option. Despite recent advances in DBS technology, a significant portion of ET patients with DBS implants will receive inadequate tremor control because of poorly placed DBS leads, while others will lose efficacy of the therapy after 1-2 years due in part to inflexible neurostimulator programming options. There is a strong and growing clinical need for implantable DBS lead designs and programming algorithms that can enable clinicians to better sculpt electric fields within the brain, especially in cases where stimulation through a poorly placed DBS lead results in low-threshold side-effects. Our proposed study will integrate high-field magnetic resonance imaging, histological neurotracing of fiber pathways, computational modeling of DBS, and single-cell electrophysiology methods to further develop and experimentally-validate a novel semi-automated machine learning algorithm that facilitates hypothesis-driven determination of subject-specific neurostimulator settings through directional DBS leads. Specifically, we will: 1) identify the neural pathways involved in the reduction of action and postural tremor using directional DBS leads and a novel particle swarm optimization algorithm based on subject-specific anatomy; 2) quantify how tremor-related information is modulated on the single-cell, population, and network levels by therapeutic DBS in a preclinical large-animal model of harmline-induced tremor; and 3) investigate how therapeutic windows (i.e. the threshold difference between postural and action tremor abolishment and side effect emergence) change over time with human DBS therapy targeting one or more pathways within the cerebello-thalamoc-cortical network. Together, this project will (a) experimentally evaluate and translate a novel DBS programming algorithm to human ET patients, (b) provide a much more detailed map of the neural pathways underlying the therapeutic effects of DBS (on postural and action tremor) and side effects of DBS (on dysarthria, paresthesia, ataxia), (c) rigorously investigate how DBS for treating tremor works mechanistically at the single cell and network levels within the brain, and (d) probe the neural pathways involved in the worsening of tremor symptoms for ET patients over time.

ABST RACT 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.