Rao P. Gullapalli - US grants

There is a large disparity in the literature regarding the effect of age on perception of pain. Various studies have shown both an increase and a decrease in pain sensitivity with age. Studies also exist that have reported no signficant change in pain sensitivity with age. A number of cerebral structures that receive and process nociceptive input originating from the body including the post-central gyrus (primary somatosensory cortex - $1), the posterior parietal operculum ( which includes the secondary somatosensory cortex - $1), the insula, and portions of the anterior cingulate cortex have been identified in mammals by various neuranatomical and neurophysiological studies. The overall objective of this study is to use quantitative psychophysics and functional MRI (fMRI) techniques to determine whether age influences the cerbral activation patterns associated with noxious mechanical stimulation. One component of this project is to determine the effect of age on suprathreshold pain perception using standard psychophysical testing methods. A second aim of this project is to determine the effect of age on cortical processing of nociceptive information. Specifically we would like to understand the processing of stimulus intensity encoding with age, the extent of involvement of the cerebral cortex, and the latency in the hemodynamic response between the young adults and the elderly. A third aim is to determine whether age differences influence variability in the fMRI response, and whether such variability (both intra- & inter-subject) impacts fMRI analysis & interpretation. We propose to test this hypothesis on two distinct age groups in the age range of 18-30 years and 55-70 years. FMRI data from the individuals would be obtained multiple times from which functional reliability maps will be generated for each subject. Individual data will then be grouped into each of the two age ranges and quantitative information on the above parameters will be generated and compared with the psychophysical pain ratings. To date their have been no studies looking into the effect of age with nociception processing using functional brain imaging. It is anticipated that the results from this project will enhance our knowledge of how the pain related processes change with age.

DESCRIPTION (provided by applicant): The University of Maryland, Baltimore currently has 18 NIH funded research projects that could greatly benefit from the availability of a shared high-field animal imaging magnetic resonance system. The projects cover a wide array of high impact, cutting edge biomedical research including topics such as, brain development and disease processes through diffusion tensor imaging, understanding brain metabolism involved in white matter disease, understanding progression of breast and prostate cancer and studying the efficacy of therapeutic agents, the pathogenic mechanisms of human herpesvirus, tumorigenesis, the progression of neurodegenerative events and studying the long and short term consequences of pharmacological treatment, the neuronal mechanisms of pain, cardiac dynamics, metabolic and development aspects of mental retardation, development of drug delivery agents for effective treatment of cancer, and many other such projects that are state-of-the-art and push the envelope of our scientific knowledge. The availability of a shared 7 Tesla animal MRI would allow investigators to probe into basic biological processes, understand the progression of disease, and follow the effects of novel pharmacological interventions through the use of multi-nuclear spectroscopy and imaging. The purchase of a 7.0 Tesla animal imaging system will be an important component to our existing shared resources on campus and will complement the high resolution NMR spectrometers that are used primarily for studying biological structures. This imaging resource will be located in specially designed space, in close proximity to the animal holding area and right next to two animal surgical suites. The Schools of Medicine, Pharmacy, and Dentistry, the Greenebaum Research Center, and the University of Maryland Biotechnology Institute join together in this shared instrument application. Institutional commitment for supporting the expenses and responsibilities for its operations will also be shared by the different schools and institutes of this campus. The number and quality of biomedical research projects performed at the University of Maryland Baltimore campus has reached a level that will guarantee a continued and pressing need to a high-field animal imaging system.

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[unreadable] DESCRIPTION (provided by applicant): Researchers from across the campus of University of Maryland, Baltimore request funding for the purchase of Advanced Functional MRI hardware and software to enhance a 3.0 Tesla research-dedicated magnet. This newly-acquired research magnet has capabilities limited to its primary project, which is to scan knees as part of a multi-center Osteoarthritis initiative. While the scanner itself is state of the art equipment, its associated tools are very limited, and will not foster the growth of magnetic resonance research on this campus. Additionally, the scanner is idle for the most part even after fulfilling its primary objective of producing structural images of the knee joints. The lack of suitable hardware and software on this scanner has severely limited the use of this high field magnet for research. NIH sponsored investigators who are currently using magnetic resonance imaging come from various departments within the campus including radiology, neurology, psychiatry, pharmacology, cardiology, anatomy and physiology. These researchers use the clinical 1.5 Tesla scanners operated by the University of Maryland Medical System during limited hours to conduct their research. Availability of hospital scanner time for research has become increasingly difficult over the past few years due to growing clinical demand. This restrictive situation has led some of the investigators to move their research to neighboring institutions. No time is available on the hospital scanner for new investigators. The new research-dedicated 3.0 Tesla machine promises to change this situation for biomedical magnetic resonance by enhancing the research of current investigators, and increasing access to much needed MR instrumentation for new investigators. The proposed upgrade to the instrument promises to advance research in the area of human brain function through use of techniques such as fMRI, diffusion tensor imaging, and spectroscopy. The capability of performing such research in conjunction with parallel imaging with optimized coils will allow the magnetic resonance research community at the University of Maryland, Baltimore to be at the forefront of functional neuroimaging research. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Fourteen investigators with 14 RO1 projects, 2 UO1 and one PO1 projects from the University of Maryland, Baltimore are requesting funds for the acquisition of a small animal PET/CT to advance their research in the areas of oncology, neuroscience and pharmacology. Small animal PET/CT provides unique opportunities for the study of animal models of disease and is a key component towards our aim of translating research from the laboratory to clinical application. The non-invasive, three- dimensional nature of the combined modality allows whole-animal biodistribution studies to be performed over an extended period of time in the same animal. Furthermore, the quantitative nature of PET/CT allows for powerful disease progression studies. These advantages will be exploited by our current and future NIH-funded investigators who will gain access to this technology as a shared resource. The proposed scanner will be housed in a dedicated animal imaging facility which currently accommodates a 7 Tesla animal MRI scanner. Much of the logistical support for the new scanner is already in place in the animal imaging facility and the addition of PET/CT is expected to compliment the high resolution anatomical images obtained from MRI. The Inveon MultiModality system from Siemens Molecular Imaging division has been selected for this project. This system is chosen because of its versatility to operate as independent single units or as a combined unit. The PET aspect of this unit provides high spatial resolution, sensitivity and count rate performance and has transmission imaging capability. The CT aspect of this instrument will provide high resolution anatomical images at a large field of view and will allow for PET attenuation and scatter correction. Researchers will be able to draw upon the considerable experience within the Radiology department in the field of diagnostic imaging, in particular imaging study design and quantitative image analysis. Administrative oversight of the scanner will be handled by a committee which will oversee financial management, staffing, instrument maintenance, training of researchers and scanner availability. Recognizing the growing role of molecular imaging and translational research the institution has made substantial commitment to the acquisition of the PET/CT system. The proposed animal PET/CT scanner is a much-needed resource which will benefit current researchers and will also stimulate future collaborations between different groups within and beyond the University of Maryland Medical System. [unreadable] [unreadable] The proposed small-animal PET/CT scanner will aid researchers in understanding animal models of disease and the efficacy of potential treatments. In this way the animal scanner will help translate the findings of basic science research to applications in humans. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Organophosphorus (OP) pesticides are among the most heavily used pest control agents worldwide. In the US, malathion and chlorpyrifos account for more than 50% of the millions of pounds of OP pesticides used yearly. An ever growing body of epidemiological studies report that children whose mothers have been exposed to OP pesticides, including chlorpyrifos and malathion, during pregnancy present higher incidence of cognitive impairments, attention deficit/hyperactivity disorder, and autism spectrum disorders than non-exposed children. Although animal studies have confirmed that in-uterus or early postnatal exposure to chlorpyrifos compromises the brain development of rats and mice, the distinct temporal course of brain development and high levels of circulating carboxylesterases (enzymes that inactivate OP compounds) make these rodents inadequate models of human OP toxicity. In addition, even though concerns regarding the toxicity of OPs to the developing brain have been substantiated by their prompt permeation through the placenta, there have been no animal studies addressing the potential developmental toxicity of malathion. The present project is designed to test the central hypothesis that the developmental neurotoxicity of malathion and chlorpyrifos in guinea pigs - the best non-primate model of human OP intoxication - can be counteracted by galantamine and is largely accounted for by epigenetic mechanisms. Galantamine, a drug approved to treat Alzheimer's disease, is known to safely and effectively protect guinea pigs against the acute toxicity of OP compounds [PNAS 103: 13220, 2006]. Galantamine can also prevent the delayed cognitive dysfunctions that result from a single exposure of guinea pigs to sub-toxic doses of OPs. This project uses a multidisciplinary approach that involves electrophysiological, behavioral, magnetic resonance imaging and molecular biological assays to address three specific aims: (i) to identify, at various postnatal ages, neurological, structural, and neurobehavioral correlates of in-uterus exposure of guinea pigs to malathion or chlorpyrifos, (ii) to determine the effectiveness of postnatal treatment with galantamine to counteract the developmental toxicity of those pesticides, and (iii) to examine the contribution of epigenetic mechanisms to the developmental toxicity of the pesticides and the therapeutic effectiveness of galantamine. The overarching goal of this project is to provide fundamental and timely input for assessment and adequate treatment of the human developmental toxicity of malathion and chlorpyrifos. The results of this highly translational study of the potential health risks associated with exposure of the immature brain to pesticides will be far reaching as they will lay the groundwork necessary to advance research aimed at identifying novel therapeutic strategies to treat neurological diseases derived from in-uterus exposure to specific OP pesticides.

Project Summary This R01 project builds on a highly successful R21 project which involved the development and feasibility of a Minimally Invasive Neurosurgical Intracranial Robot (MINIR-I) using shape memory alloy (SMA) actuators as well as the evaluation of the device under continuous MRI for resection of an implanted ?metastatic tumor? in swine brain. While we achieved the specific aims of the R21 project, we also discovered new challenges, which are the basis for this R01 application. Brain tumors are among the most feared complications of cancer occurring in 20?40% of adult cancer patients. Despite numerous advances in treatment, the prognosis for these patients is poor, with a median survival of 4?8 months. Whether a primary (intrinsic) malignancy, or a secondary (metastatic) malignancy, involvement of the brain in a cancer patient is devastating, because it threatens the very personality and identity of the individual, and is invariably the most likely of all complications to directly and severely affect the quality of life. Currently, the optimal treatment for most brain tumors involves primary surgical resection to facilitate adjuvant therapies such as radiation and chemotherapy. Unfortunately, many patients cannot undergo primary surgical resection of their brain tumor due to unfavorable location of the lesion (usually deep or otherwise inaccessible to conventional neurosurgical techniques), and poor general health of the patient. To address this problem, based on the success of our R21 pilot project, and the lessons learned therein, we propose to develop a fully MRI-compatible MINIR-II and demonstrate the safety and efficacy of MINIR-II through comprehensive assessments on clinically relevant ex vivo and in vivo swine and followed by human cadaver models. As envisioned, MINIR-II will be under the direct control of the physician, with targeting information obtained exclusively from real-time MRI that uses active targeting methods with the sensors embedded within MINIR-II. To realize MINIR-II, we will address four specific aims: 1) Design a fully MRI compatible multiple degree-of-freedom (DOF) MINIR-II of rigid plastic body with cable driven joints, hollow inner core for routing cabling and electronics, irrigation and suction capability, and tumor removal capability, 2) Develop and characterize a multi-piece mold capable of molding geometrically complex robot links with miniature features to produce a completely disposable/single use MINIR-II prototype, 3) Develop a tracking and navigation system for MINIR-II that will allow visualization of proximal and distal structures for accurate targeting and resection of the tumor, and finally 4) the safety and efficacy of MINIR-II in gelatin phantoms and clinically relevant models of metastatic brain tumor including, a cadaveric pig model, a live pig model, and a human cadaver model. Our goal at the end of this project is to have MINIR-II (operated under continuous MRI) ready for clinical trials.

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a major cause of death and disability in both civilian and military populations. Several publications regarding TBI including those involving imaging have hinted towards potential clinical and imaging biomarkers. However, no clear picture has emerged regarding the prognostic value of these biomarkers or imaging markers that could be used to initiate drug development and validate novel therapeutic interventions. Thanks to the efforts of NIH and the DOD, in recent years there has been a tremendous growth in TBI imaging research across the nation and worldwide. We have been fortunate to participate in TBI research since early 2000's, which has generated significant amount of clinical, behavioral and advanced MR imaging data. We and the larger TBI research community would significantly benefit if we pool our data into a single unified database such as the FITBIR information system. This would provide us access to a large amount of data that is not possible to generate at single site, and allow individual investigators to test their hypothese using novel algorithms. This may be the only way to arrive at imaging markers that have high sensitivity and specificity for a disease that can take such variable paths. Besides data from conventional MR, the imaging data that we can provide to FITBIR includes advanced imaging techniques such as diffusion tensor imaging, diffusion kurtosis imaging, MR spectroscopy, arterial spin labeling, high-resolution volumetrics, susceptibility-weighted imaging, and resting state and task based fMRI. In addition, we will also be providing longitudinal imaging data across 18 months (four total time points) on a subset of these patients. We are also interested in testing our preliminary findings from our study to determine if our results extend to larger datasets from various other institutes given their own experimental variations. The effect of an impact to the head on any given location can have varied consequences, and will depend on several factors including the acceleration forces involved, type of injury (whether mechanical or blast), and the demographics of the patient. Therefore, a clear picture can only emerge from studies with much larger sample sizes to account for the heterogeneous disease processes. A database such as FITBIR which is poised to collect data from various investigators and continue to add data from future research projects would be enormously beneficial to individual researchers interested in various aspects of TBI. As a group, we have already been trained on the use of FITBIR and are familiar with creating new common data elements and unique data elements when necessary. In addition we will benefit from FITBIR by having access to larger amounts of DTI, resting state, and volumetric data to further study the role of the thalamus and the mid-brain and to understand the involvement of different brain networks that leads to both neurodegeneration and reparation. It is hoped that we and other TBI researchers alike can benefit from this large database to identify clinical and imaging biomarkers that can lead to the development of novel therapies and can be used to monitor the effects of such therapies longitudinally.

10.0 Abstract: Imaging Shared Service The mission of the Imaging Shared Service (ISS) is to provide a wide array of state-of-the-art imaging services that permit structural and functional imaging of cells, whole animals, and humans. Major goals include offering UMGCC investigators access to a wide range of imaging modalities and instrumentation; providing onsite expertise to aid experimental design, execution, data processing, and data analysis; and providing an environment that fosters collaboration and innovation and encourages clinically relevant studies. An additional important goal is UMGCC investigator training, as the ISS is committed to broadening the knowledge of the institutional faculty, staff, fellows, and students regarding state-of-the-art imaging technology. The ISS is a new UMGCC shared service that permits studies ranging from cells to mouse to whole body clinical imaging. Because of demand for these services, the ISS has grown rapidly in a short period of time. Moreover, the translational research component of the ISS has increased significantly, with more users focused on translating discoveries to the clinic. In 2014, the ISS supported 79 Cancer Center members, 43 percent of whom have peer-reviewed funding. ISS users (31 percent of all UMGCC members) spanned all 5 research programs. The ISS supports many cancer- related publications annually, many in high-impact journals including Cancer Research and JAMA.

ABSTRACT/PROJECT SUMMARY Several preclinical & clinical studies have implicated that acceleration/deceleration forces to the brain beyond a certain threshold can lead to disruption of both axonal microtubules and vascular endothelium. The consequences of such injury include diffuse axonal injury and transitory blood flow impairment at the acute stage and the accumulation of toxic protein species such as phosphorylated tau over time, a key factor in the development of vascular cognitive impairment and dementia. In addition, it is thought that the AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric symptoms, attention deficits, sleep disturbances, oculomotor dysfunctions and altered pain perception. A brain wide ?glymphatic system?, driven by arterial pulsatility, comprised of paravascular pathways and meningeal lymphatic channels is now recognized as a major pathway of clearance of these proteins from the brain. This pathway, tightly temporally correlated to sleep, has recently shown to be affected by TBI. The thalamus plays a well- known role in sleep regulation. We therefore posit that a likely ?vicious cycle? exists wherein glymphatic pathways disrupted by TBI fail to clear toxic protein species from the thalamus, affecting its structure and function, resulting in sleep dysregulation and thereby, impaired glymphatic efflux. As a supplement to the parent grant which is focused on examining the longitudinal changes in the structural and functional connectivity of the thalamus after TBI, we wish to examine, using advanced MRI techniques, whether symptoms of TBI arise from an interplay between thalamic injury and impaired glymphatic efflux. We hypothesize that vascular impairments following TBI include not only endothelial damage but also extend to glymphatic disruption and meningeal lymphatic injury and that such disruption will differentially affect thalamic structural and functional connectivity. Using advanced imaging techniques, we propose to address this using the following two aims: (1) we wish to examine in vivo, using MRI, differences in the structure and function of the human glymphatic system spanning the perivascular space to the meningeal lymphatics between patients with mild TBI and age and gender matched control subjects both at the early (~6mo) and late stages of injury (~5y after initial injury). In Aim 2 we will assess the influence of glymphatic dysfunction upon global thalamic and individual thalamic nuclear structure and thalamocortical structural and functional connectivity and upon performance on neuropsychological assessments. The results from this study will provide a unified framework to understand mechanisms that lead to not only TBI related dementia, vascular cognitive impairment and Alzheimer?s disease but also those that arise from toxic protein accumulation such as Frontotemporal dementia and Lewy Body Disease among others.

ABSTRACT Poisoning with organophosphorus (OP) pesticides during gestation is a life-threatening condition for both mothers and fetuses. Treatment relies heavily on the use of high doses of atropine to block muscarinic receptor overactivation by acetylcholine (ACh) build up due to OP-induced block of acetylcholinesterase (AChE). However, despite therapeutic intervention spontaneous miscarriages, infant and/or maternal deaths, and postnatal neurological complications (including seizures and cognitive deficits) can ensue. Although rarely taken into account, the non-selective inhibition of all muscarinic receptor (mAChR) subtypes by atropine may be an important determinant of these poor outcomes. Specifically, inhibition of presynaptic mAChRs (mostly M2), which are part of a negative feedback loop that limits ACh release from cholinergic neurons, can exacerbate the OP-induced cholinergic crisis. The pharmacological profile of R,S-trihexyphenidyl (THP), a drug that has been safely used during pregnancy and is approved for treatment dystonia and Parkinson?s disease, makes it an attractive candidate to treat gestational OP poisoning. In contrast to atropine, THP more selectively inhibits M1 and M3 than M2 mAChRs. In addition, THP inhibits as-of-yet unidentified subtypes of neuronal nicotinic ACh receptors (nAChRs). Overactivation of M1/M3 mAChRs and neuronal nAChRs in the placenta and myometrium, and in the cardiorespiratory and nervous systems can contribute to poor health outcomes following acute OP intoxication during pregnancy. Thus, this project will test the hypothesis that, in part by sparing M2 mAChRs and potentially by blocking nAChRs in addition to M1/M3 mAChRs, THP will be more potent and efficacious than atropine to treat gestational OP poisoning. The focus will be on chlorpyrifos (CPF), a widely used OP pesticide currently included in the U.S. Department of Homeland Security Chemical Threat Risk Assessment list of chemicals that may be deployed to poison large numbers of people in terrorist attacks. A multidisciplinary approach, a translationally relevant animal model (the guinea pig), and a placebo-controlled, randomized, blind design that minimizes experimental bias and maximizes scientific rigor will be used to address three aims. Aims 1 and 2 will establish the effectiveness of THP to save lives, reduce signs of acute toxicity, and prevent the development of neurological complications in mothers and fetuses gestationally exposed to a high dose of CPF. Aim 3 will shed light on the mechanisms that contribute to the toxicity of CPF and the antidotal effectiveness of THP. Successful completion of this project will lay the groundwork for the development of more effective antidotes to treat acute CPF intoxication during pregnancy. Identification of therapeutic interventions that can have a positive impact on the health outcomes of populations acutely intoxicated with OP pesticides lends support to the initiative of the World Health Organization to tackle the issue of acute OP pesticide intoxication, particularly in the developing world. In addition, it fulfills an unmet medical need for the effective treatment of victims of a deliberate attack with these pesticides.

It is well-recognized that unanticipated respiration-induced motion can result in significant errors in planned vs delivered dose in thoracic radiotherapy (RT), resulting in local regional failure and/or increased radiation-induced toxicity. In this proposal, we build upon our previous motion management research and aim to overcome the limitations of current motion management strategies, which tend to underrepresent both the extent and the spatiotemporal complexity of respiratory motion. Our overall premise is that, as our field adopts increasingly more potent forms of RT, real-time single-point monitoring needs to be replaced by real-time volumetric monitoring to capture complex motion. Recently available integrated magnetic resonance imaging (MRI)+Linac systems aim to address the limitations of current conventional solutions. However, the high cost and complexity of these systems, as well as engineering and technological challenges, have proven to be substantial barriers to their widespread clinical adoption (less than 1% of the total US install base for linacs). To address this unmet clinical need, we form an academic-industrial partnership to investigate and develop a novel in-room real-time motion management solution for lung RT that combines 4DMRI and 4DCT (4D=3D+time). In Aim 1, we develop and investigate rapid 4DMRI techniques. In Aim 2, we merge the volumetric motion information derived from 4DMRI and 4DCT to create a patient-specific, multi-cycle motion model that incorporates the geometric fidelity and electron density information from CT with the soft-tissue contrast and dose-free, long-term monitoring from MRI. This model is parameterized by the spatial positions of MRI-compatible electromagnetic (EM) sensors placed on the thoracoabdominal surface of the patient. By knowing the position of these sensors at any given time point, we can estimate the corresponding position of each voxel within the irradiated volume. At each treatment fraction, the model is rebuilt using in-room kV fluoroscopy prior to delivery to account for inter-fraction (day-to-day) changes in external-internal correspondence and updated using kV fluoro during dose delivery to account for intra-fraction changes. In Aim 3, we develop two identical preclinical prototype systems (EndoScoutRT) and form end-user teams tasked with formulating clinical workflows, quality assurance guidelines, and strategies for clinical translation. In Aim 4, we perform end-user evaluation of the prototype systems by conducting a prospective non-interventional clinical study in 44 lung cancer patients at two institutions. We compare the performance of our model-based motion management to current standard-of-care and MRI+Linac based real-time motion management. Our team has extensive expertise in clinical study design, image-guided RT, rapid MRI, and real-time motion management. We anticipate that the successful clinical translation of this approach (beyond the current scope) will enable safer administration of highly potent and clinically effective forms of thoracic RT.