1995 — 1997 |
Apkarian, Apkar Vania |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training in Computational Neuroscience |
1.009 |
1996 — 2013 |
Apkarian, Apkar Vania |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cortical Pathophysiology of Pain @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): Current understanding of the development of chronic back pain is rudimentary. In the last funding period our work focused on discovering brain-derived biomarkers typifying clinical chronic pain conditions. We uncovered a specific set of markers that not only distinguish chronic pain patients from healthy subjects, but also differentiate among various chronic pain conditions. In this next phase of study we intend to use these biomarkers to define - for the first time - temporal changes in brain physiology, anatomy, and metabolism that accompany the transition from sub-acute to chronic pain, and to distinguish predictive markers from those that are a consequence of the chronic pain. We will also identify which of these parameters reverse when the pain subsides, thereby determining if brain injury caused by chronic pain will be transient or permanent. In Aim 1, we longitudinally track brain morphology, brain physiology, and brain metabolic markers in subacute back pain patients for 18 months as they transition to either chronic pain or pain resolution. Changes in brain biomarkers are studied as a function of the final pain state (chronic vs. resolution) and of the time from subacute pain state. Hypotheses are advanced regarding changes in these markers based on our results in cross-sectional studies. In Aim 2, we build a predictive model for assessing one's risk for transitioning from subacute to chronic back pain based on the results of Aim 1. In this aim we pool the outcome measures and use them together for predicting transitions to chronic pain and to pain resolution, as well as for predicting the clinical characteristics of subacute and chronic pain. In Aim 3, we perform a cross-sectional case-control study to determine brain morphology, brain physiology, and brain metabolic markers in chronic back pain patients who have been in the condition for at least five years, and contrast these parameters to both the subacute population studied in Aim 1 and to matched healthy control subjects, in order to determine which parameters progress as chronic pain is sustained for several years. Our previous cross-sectional studies show that the brain plays a prominent role in chronic back pain. Here we test the involvement and causative role of brain biomarkers in the progression of back pain from a subacute to a chronic state. PUBLIC HEALTH RELEVANCE Chronic back pain is a major health problem and there is little understanding of its underlying mechanisms. We have shown that many brain properties are different in chronic back pain patients in contrast to healthy controls. Here we examine these brain biomarkers as we track subjects transitioning from subacute back pain to either pain resolution or to chronic pain, over an 18 month monitoring period, and contrast these outcomes to healthy controls and to more chronic back pain patients. We also plan to build models for predicting chronic pain based on brain parameters measured in the subacute stage.
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1.009 |
2002 — 2005 |
Apkarian, Apkar Vania |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cortical Dynamics For Pain Perception in Behaving Rats @ Northwestern University
[unreadable] DESCRIPTION (provided by applicant): Pain is by far the most frequent symptom for seeking health care. However, current understanding of pain perception lags far behind other aspects of contemporary neuroscience. Tools and techniques are equally outdated relative to other areas. As a consequence and despite many important advances the objective link between pain perception and cortical neuronal activity is still missing. Recent development of technology for multi-electrode recording in freely moving animals in conjunction with the advent of novel theoretical tools of analysis seems to provide a reasonable opportunity for uncovering the causal relationship between perception of pain and cortical neuroelectrical activity. Recent human brain imaging studies (including our own) have implicated distinct cortical patterns for acute vs. chronic pain conditions. Altogether these results suggest specific hypotheses to be tested in this project. [unreadable] [unreadable] The overall aim is to find the link between dynamic patterns of cortical activity and pain perception. Rat models of acute (transient mechanical and thermal noxious stimuli) and chronic pain conditions (peripheral partial nerve injury resultant pain behavior) will be instrumented with multi-electrode recordings. We will identify cortical spatiotemporal patterns of neuronal activity previously reported during perception in other sensory and cognitive modalities. We will test the main hypothesis that perception of pain equates to synchronous activation of multiple cortical regions on an oscillatory (Gamma-like) pattern, differing in the regions involved for acute and chronic states. Neuronal population properties to painful stimuli will be studied in awake behaving rats. Interactions within and across 5 different brain areas will be studied (primary and secondary somatosensory, insular, cingulate, and orbital frontal), using local field potentials, single- and multi-unit spike activity. Overall these results should identify the link between pain perception and cortical activity objectively enough to provide a quantitative assessment of clinical pain conditions, and propose new directions for therapy, especially for chronic pain conditions.
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1.009 |
2006 — 2007 |
Apkarian, Apkar Vania |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Characterizing Temporal Dynamics of Spontaneous Pain @ Northwestern University
[unreadable] DESCRIPTION (provided by applicant): We have discovered that the pattern of temporal variability of spontaneous pain can be readily measured in clinical pain conditions, and that normal healthy subjects cannot mimic this variability. This pattern of variability was well characterized by measuring its fractal dimension 'D' of consecutive ratings of spontaneous pain. Our preliminary results suggest that D is different between chronic post herpetic neuropathy patients, chronic back pain patients, normal subjects imagining having back pain, and normal subjects rating a thermal painful stimulus. These observations suggest that temporal variability of spontaneous pain may be an objective measure of pain and may provide information regarding the dynamical processes in the nervous system. This proposal rigorously tests the latter claim in a larger population of chronic back pain patients. Specific aim 1 examines fractal properties of pain ratings in larger time windows. Specific aim 2 tests the variability of the fractal dimension and contrasts this variability with linear statistical measures, like the mean and standard deviation of present or average pain. Specific aim 3 examines the relationship between fractal properties and clinical characteristics of back pain. These experiments test the utility of measuring temporal dynamics of spontaneous pain as a new and objective tool regarding clinical pain conditions and examines the power of the technique in revealing insights regarding nervous system control mechanisms that modulate pain conditions. [unreadable] [unreadable] [unreadable]
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1.009 |
2008 — 2012 |
Apkarian, Apkar Vania |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Chronic Pain and Emotional Learning and Memory @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): This is a reverse translational project designed to unravel mechanisms underlying the impact of chronic pain on fundamental cortical functions, and to explore novel pharmacological manipulations potentially leading to novel therapeutics for alleviating neuropathic pain. The proposal is inspired by our human brain imaging studies that suggest a bidirectional interaction between neuropathic pain and emotional learning and memory, through the impact of pain on the prefrontal cortex. This project addresses these issues mechanistically in rodent models of persistent pain by 1) documenting deficits in emotional learning and memory;2) relating such deficits to prefrontal cortical neuronal activity;3) identifying the spatiotemporal pattern of brain regional changes in phenotype, in NMDA and AMPA expression, and cytokine expression, and 4) contrasting these outcomes between rodent models for neuropathic pain and persistent inflammatory pain. In Aim 1 we will examine the impact of neuropathic and inflammatory rodent models of persistent pain on emotional learning and memory, by assessing behavior on fear and reward conditioned-learning behavior. We also test the influence of chronicity of pain (that is duration from initial peripheral injury) on emotional learning and memory. We will also examine electrophysiological properties of prefrontal neurons in neuropathic rats in relation to pain and fear behaviors. Our preliminary results already indicate that neuropathic injured rats show: 1) reduced extinction of long-term fear memory, 2) reduced motivation in reward consumption, and 3) reduced reward seeking behavior;while inflammatory injured rats show reduced extinction for short-term fear memory. In Aim 2 we will study the effects of pharmacological manipulations, which modulate glutamatergic transmission in the prefrontal cortex, on neuropathic and inflammatory pain and on learning and memory. Our studies show that repeated oral D-cycloserine in neuropathic rats reduces the signs of pain behavior for weeks after stopping drug administration, 2) these effects are reproduced by acute infusion of D-cycloserine in either the medial prefrontal cortex or the amygdala, 3) acute infusion of D-cycloserine in medial prefrontal cortex completely reverses the injured paw dependent operant aversion behavior. We will extend these findings by examining effects of effects of a glycine transporter blocker (sarcosine) on the same paradigms. In Aim 3 we will study expression and role of brain-borne cytokines in neuropathic and inflammatory pain. The functional role of cytokines will be studied in persistent pain models, when cytokine receptor antagonist or cytokine blocking adenovectors are injected at specific brain sites. Recent findings indicate that brain-borne cytokines, such as IL-1 and IL-6, can affect synaptic plasticity, which depends on the stimulation of NMDA receptors. Consistently, it is also known that these mediators can affect behavior, learning and memory. Moreover, we now have results regarding cytokine expression in neuropathic rats and modulation of neuropathic pain behavior following blockade of cortical cytokines. PUBLIC HEALTH RELEVANCE: The overall purpose of this proposal is to understand the interaction between persistent pain and cortical cognitive mechanisms. The long-term objective is to develop novel drug therapies that act specifically at the cortical level and potentially reduce the suffering associated with chronic pain. Moreover, we seek to identify the role of endogenous cytokines, as markers for plasticity and learning, in the chronic pain. .
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1.009 |
2012 — 2016 |
Apkarian, Apkar Vania |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cortico-Striatal Plasticity in the Transition to Chronic Pain @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): In this application we argue that mechanisms of transition from acute to chronic pain critically depend on brain emotional and motivational learning and memory circuit, namely the properties of the corticostriatal system. This is a radical departure from the classic pain research tradition, which emphasizes mechanisms of nociceptive encoding and representation. We provide human and animal model data consistent with the idea, and propose unraveling underlying mechanisms and translating this information to clinical application by testing a drug treatment strategy for preventing transition to chronic pain We recruit Dr. Surmeier (a world renowned expert on the physiology and reorganization of the striatum) and Dr. Martina (a young scientist with expertise in molecular and electrophysiological studies of the brain), to collaborate with Apkarian on this project, and Drs. Fields and Zubieta act as consultants for the project. In Aim 1 we combine the expertise of the three collaborating labs (Apkarian, Martina, Surmeier) to link large-scale brain imaging outcomes to cellular, molecular, and electrophysiological changes that we predict the corticostriatal undergoes in the transition from peripheral nerve injury to neuropathic pain-like behavior in rodents. In Aim 2 we compare among potential drugs for preventing transition to chronic pain-like behavior in a rat model. In Aim 3 we use the best candidate drug in a human early phase clinical trial, combined with brain imaging, for prevention of transition to chronic pain. The successful completion of the study should dramatically change current notions regarding brain mechanisms of pain chronification, and provide a new concept of treatment strategy for preventing the transition to chronic pain.
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1.009 |
2013 |
Apkarian, Apkar Vania |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Brain Imaging Based Strategies For Treating Ucpps Pain @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): This is a one-year R01 application in response to RFA-DK-12-025 entitled Urologic Chronic Pelvic Pain Syndrome (UCPPS) Research (R01). There are no effective treatments for UCPPS. Recent preliminary results from the Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network indicate global and local brain anatomical and functional abnormalities in men with UCPPS. Thus, renormalization of the urological pain-related brain reorganization is a viable and objective target for treating UCPPS. Our recent human studies in other chronic pain conditions indicate that placebo alone may be an efficient treatment in some patients. Also, our animal studies show that D-cycloserine (DCS, targeting the frontal cortex) can reverse many of the signs of neuropathic pain in rodents. These results indicate that urological pain relief by placebo and by DCS are potential therapy options for UCPPS, each of which may be mediated through distinct brain circuitry. Here we test the efficacy of DCS and placebo, in comparison to each other and to no-treatment, in a double blind, three-armed, brain imaging-based randomized clinical trial in men with UCPPS. Brain anatomy and function are monitored repeatedly, and urological pain is measured with questionnaires and using a smart phone App (to collect pain ratings in the natural setting of everyday life, 3 times a day). Participants undergo a 2-week observation period, a 3-month treatment period, a 2-week washout period, and a final period wherein participants choose to continue on one of the two treatments for another month. The trial will permit us to address three specific aims: Aim 1: Evaluate differential efficacy for UCPPS urological pain relief between placebo and DCS. Aim 2: Evaluate differential brain functional biomarkers for treatment response and treatment propensity, for placebo and for DCS. Aim 3: Demonstrate that brain morphology renormalizes in treatment responders. Given the financial and time constraints of this RFA, the study is powered to be a proof of concept and to demonstrate the strength of the methodology in providing objective evidence for individualized treatment choices when evaluating novel therapies in UCPPS.
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1.009 |
2013 — 2017 |
Apkarian, Apkar Vania |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Brain Mechanisms For Clinical Placebo in Chronic Pain @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): This application is designed to examine brain properties for placebo responses in chronic back pain patients. We have preliminary data indicating that, in blinded clinical trial studies with neutral instructions regarding treatment, chronic back pain (CBP) and osteoarthritis patients can be subdivided into placebo responders and non- responders and these differences are PREDICTABLE a priori by brain activity. The results imply that CBP placebo response may have clinical utility and that its properties can be studied by human brain imaging techniques. We address these issues in three specific aims, where CBP placebo response properties are studied in a double blind clinical trial (RCT) setting. In Aim 1, we will examine the reproducibility and predictability of the propensity to placebo response in CBP patients. Brain anatomy and function are assessed prior to the start of the RCTs and at different time points during the trial. Additionally, pain and quality of life profilesare collected throughout the trial, using smart phone technology monitoring to acquire these parameters in a naturalistic setting. Brain biomarker outcomes and predictions are contrasted between CBP placebo responders and non- responders, and compared to no treatment. Washout periods are used to test for reversibility of placebo responses. In Aim 2, we study the interaction between placebo and medication treatment, and validate the predictability of placebo propensity in CBP. In Aim 3, we develop a self-report measure to predict placebo propensity based on correlations with neuro-imaging biomarkers. Overall, these studies are designed to critically assess the neurobiology of placebo analgesia for chronic pain within the setting of clinical trials, and creating a readily available clinically useful instrument to identify placebo responders. If successful, the completion of the outlined studies has the potential to dramatically alter health care in chronic pain.
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1.009 |
2018 — 2021 |
Apkarian, Apkar Vania |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Administrative Core @ Northwestern University At Chicago
Abstract Admin Core The major aim of this core is to coordinate program budget, activities, and training, facilitate communication between program participants, and coordinate a small Pilot Projects Program (PPP). In particular, this core will coordinate: 1) program budget/subcontract arrangements, 2) biannual meetings of P.I.s, key program personnel, patient advisory board, and external advisors, 3) archiving and distribution of program publications, 4) compilation and submission of annual NIH program renewal applications, 5) data management and compliance with NIH policies, 6) maintenance of a program web page, 7) training of graduate and postdoctoral students, and educational outreach (lectures, etc.), 8) organize a structured review for pilot project applications, and disseminate and monitor progress of PPP funded projects. The overall administration and direction of the program project will be the responsibility of the Program Director A. Vania Apkarian. The routine day-to-day administration of the program, including budgetary matters, correspondence and meetings will be managed by the Administrative Assistant. Educational matters will be managed by co-PI J. Griffith, who will oversee academic opportunities for students, fellows, and trainees, and organize the Pilot Projects Program. The Program Director and Project Principal Investigators will make budgetary and scientific decisions pertaining to individual projects jointly. These decisions will be made four times a year. In addition to business matters, these meetings will offer investigators participating in each project an opportunity to discuss their projects, and evaluate experimental progress. Although each meeting will focus on an individual project on a rotating basis, this structure will remain flexible to allow new discoveries to be discussed. Existing technologies will enable these conferences to take place from networked workstations. This will provide an opportunity to share data in a variety of formats and stages of analysis. All project leaders are in close proximity on the Northwestern Medicine campus in downtown Chicago, allowing for routine weekly interactions. The program will be reviewed by Internal, Patient Advisory Board, and External Advisory Committees. Our Internal Advisory Committee (IAC) is composed of experts in drug abuse prevention, clinical pain management, opioid pharmacology, chronic pain and cellular/molecular/genetic physiology, and are all affiliated with the Feinberg School of Medicine. Chris Weasley and Terrie Cowley will lead our patient advisory board (PAB). They both have experience with national advocacy and will advise our program. The IAC and PAB will meet with the Center Director and team leaders twice a year to discuss the scientific progress of the Center, governance and administration issues, and evaluate proposals for the Pilot Projects Program. Additionally, a four-member External Advisory Committee will review the center annually. Once a year, these consultants will spend two days evaluating program progress and providing advice. Each consultant will provide a written report after visiting. This report will be distributed to the members of the center. If needed, remedial plans will be formulated, implemented and documented.
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1.009 |
2018 — 2021 |
Apkarian, Apkar Vania |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Brain Reorganization in Chronic Back Pain and Opioid Exposure @ Northwestern University At Chicago
Abstract: Project 1, Adaptations of the brain in chronic pain with opioid exposure The current opioid epidemic is intimately linked with the clinical management of chronic pain. 15-20% of the US population suffers from the condition, and a sizable proportion of such patients are managed with opioids. Chronic back pain (CBP) is the most common chronic pain condition in the US. Research in the Apkarian lab has shown that brain addiction circuitry (mesocorticolimbic system), critical in opioid use disorder (OUD), is also causally linked to the development of chronic pain. Thus, an overarching hypothesis of this Project, and of our Center, is that opioid abuse liability and the development of chronic pain are interacting brain processes, and critical to explaining clinical outcomes of abuse liability and the loss/moderation of analgesic efficacy. Yet, there is virtually no human or rodent brain imaging evidence on the topic, and physiologic knowledge regarding the interaction between chronic pain, opioid analgesia and abuse liability is minimal. In this project, we will study brain reorganization and behavioral responses in chronic pain with opioid exposure, both in CBP and in a rat model of chronic pain (SNI). Aim 1a will study four groups: i) individuals with CBP managed with opioids and no signs of misuse (n=80); ii) patients with CBP and mild to moderate OUD (mOUD, n=80); iii) patients with CBP managed without opioids (n=25); and iv) healthy controls (n=25). We will track daily analgesic drug consumption and pain and craving reports over 1-2 weeks. In a single scan session, we collect brain anatomical and functional data (resting state fMRI, T1, DTI, ASL) to elucidate the neural correlates of pain, analgesia, and abuse liability. In Aim 1b, all participants from aim 1a will be assessed for motor, cognitive and emotional abilities (NIH Toolbox). Aim 1 results should distinguish between opioid resilient and vulnerable groups, and unravel the impact of opioid exposure on abilities and related brain maladaptations. In Aim 2a, 50% of the patients from groups i and ii (n=40/group) will be enrolled into a placebo-controlled drug withdrawal and re- exposure study. Opioid drug dispensing is delayed to provoke craving and/or increased pain, and participants are scanned during psychological withdrawal and after re-exposure. Re-exposure will involve their opioid drug, placebo, or sinemet and naproxen (DA+NSAID, a potential novel treatment), in a double-blind, randomized, cross-over design. Aim 2b will assess changes in motor, cognitive and emotional abilities at different phases of opioid withdrawal and re-exposure. Aim 2 data will differentiate circuitry for analgesia/hyperalgesia and OUD, test the effects of DA+NSAID on the brain, and the dependence of abilities on opioid states. Aim 3 will track brain activity and functional connectivity reorganization (rsfMRI and FDG PET), in SNI vs. sham rats, +/- morphine exposure. In some rats, brain imaging will be combined with viral chemogenetic manipulations to unravel circuit- and cell- type specific reorganization (for VTA, NAc, and dH). Aim 3 data will provide cross- species correspondences, linking human and rodent circuit adaptations, and establish in-vivo translational validity for the mouse in-vitro studies in Projects 2-4.
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1.009 |
2018 — 2021 |
Apkarian, Apkar Vania |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Center For Chronic Pain and Drug Abuse @ Northwestern University At Chicago
Abstract Overall, Center for Chronic Pain and Drug Abuse: This is a resubmission of a P50 application, PAR-16-009, to launch a Center for Chronic Pain and Drug Abuse. Our Center proposal is built on the recognition that opioid addiction and chronic pain engage the same brain circuitry, the mesolimbic system. Although opiates continue to be prescribed to millions of chronic pain patients, and chronic pain is a primary contributor to the ongoing opiate epidemic, there is virtually no scientific knowledge regarding mechanisms that control the interaction between chronic pain and opioid exposure. Our Center is organized to uncover mechanisms that causally control this interaction, and to aggressively search for critical molecules, circuits, and biomarkers, and ultimately, novel non-addictive treatment options for chronic pain. Our overarching hypothesis is that the chronic pain state primes limbic circuitry for opiate abuse, and also, that associated adaptations depend on the duration and dose of both chronic pain and opioid exposure. The hypothesis will be rigorously tested using an array of cutting-edge tools, to study the underlying mechanisms from the scale of genes to molecules, circuits and whole-brain anatomy and function. Patients with chronic back pain (CBP) are the largest and best characterized group of humans at risk for opioid abuse disorder. Project 1 will use advanced brain imaging approaches to study brain properties in CBP, and in a rat model of chronic pain (SNI), for opioid exposure. The human studies will be 1) cross-sectional, comparing brain anatomy and function between groups; and 2) within-subject, examining brain activity and network properties during brief opioid withdrawal and re-exposure to placebo, opioid, or dopamine. The study seeks to identify: biomarkers for opioid use disorder (OUD); brain distortions and cognitive, emotional, and motor changes associated with opioid exposure; and the role of dopaminergic circuitry in OUD and opioid analgesia. Parallel brain imaging in rats with chronic pain (SNI) and with morphine exposure (MSA or MCPP) will establish cross-species correspondences, and interrogate circuitry studied in Projects 2-4. Project 2 will focus on circuits involved in motivation and addiction (mPFC, NAc, VTA); Project 3 will focus on episodic memory and relapse for opiate seeking (dorsal hippocampus, dH, interaction with VTA and cortex); Project 4 will focus on genetically defined single-cell adaptations for the mesolimbic region underlying opioid reinforcement (VTA and its connectivity to NAc and dH), searching for novel molecular targets to control chronic pain. All animal studies will use the same model for chronic pain. Projects 2-4 use genetically modified mice; Projects 2, 3 use opto- and chemo- genetics, and electrophysiology; and Project 4 uses single cell transcriptomics. The rodent behavior core will generate SNI rodents with MSA or MCPP for all projects. The computational and statistics core will provide data processing support, and enable data sharing with the research community at large. The administrative core will oversee the organizational, and educational missions of the program, including the pilot projects element, which will fund small projects from junior scientists to accelerate the Center?s science. 1
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1.009 |
2019 — 2021 |
Apkarian, Apkar Vania |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Brain Pathophysiology of Osteoarthritis Pain @ Northwestern University At Chicago
Abstract: This is a revised proposal in response to PA-18-141 and the NIH HEAL initiative, designed to unravel mechanisms that underlie chronic osteoarthritis (OA) knee pain. OA is the leading musculoskeletal chronic pain condition worldwide, yet little is known about the mechanisms of chronic OA pain, reflected in the fact that current pharmacologic approaches are minimally effective and new treatments have not been developed. In contrast, joint replacement surgery is highly effective in most, but not all, patients with OA. For unknown reasons, around 20% (>140,000 cases in 2017 in the US alone) of OA knee replacement surgeries (TKR) fail to relieve pain. We and others have shown that in people with chronic OA pain, the brain shows maladaptive reorganization of the neocortex, diminished volumes of sub-cortical limbic structures, distinct brain activity for OA pain, and global disruption of functional information integration. Together these results imply altered personality, psychosocial status, and abnormalities in abilities for cognition, emotion, sensation and motor function (CESM-abilities), which to our knowledge remain essentially unexplored in OA. In addition, nociceptive processes (peripheral and central sensitization, descending modulation) have been considered as possibly being important for chronicity of OA. Hence, the primary goals of this proposal are (1) to characterize the neurologic mechanisms for chronic OA knee pain, and (2) to define neurologic mechanisms that differentiate success and failure of TKR. We propose testable hypotheses regarding mechanisms underlying chronic OA pain and those that control TKR outcomes. In Aim 1, we will study a large group of OA pain patients prior to TKR, as well as OA pain patients not undergoing TKR (positive control) and healthy individuals (negative control), to characterize brain circuitries (T1, DMRI, resting state fMRI) and determine how these map to nociception, to pain and related psychosocial status, personality, and CESM-abilities. Since ~80% of TKR are successful in the long term (12 months), we hypothesize that in these cases, the dominant parameter controlling pain is the OA joint-related nociceptive processes; while in cases where TKR fails in the long term, there is a stronger dependence on psychosocial attributes and personality (based on limbic brain properties). The latter hypothesis will be tested both over the short term (3 months post-TKR in Aim 2A) and in the long term (12 months post-TKR in Aim 2B), by constructing models from pre-TKR measures (collected in aim 1) to predict knee pain in the short and long term after TKR. In Aim 3, subgroups of patients with the greatest and least pain relief at 3 months post-TKR will be fully reassessed for outcomes deemed relevant (in Aim 1), followed, and then reassessed again at 12 months post-TKR. Outcome contrasts between groups, and within groups in time, will allow us to identify consequences of knee surgery. These outlined studies expand on our current knowledge regarding mechanisms of chronic pain in general, and more specifically for OA and for post-TKR pain, potentially unraveling novel therapeutic targets.
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1.009 |