2014 — 2015 |
Loggia, Marco Luciano |
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.) |
The Role of Neuroimmune Activation in Chronic Pain and Negative Affect @ Massachusetts General Hospital
DESCRIPTION (provided by applicant): Microglia are a normally dormant subpopulation of macrophages, which rapidly activate in response to a variety of pathological conditions (e.g., inflammation, neurodegeneration), to enable the destruction of invading micro-organisms, the removal of potentially deleterious debris and the promotion of tissue repair. However, animal studies have now convincingly shown that this reaction becomes uncontrolled in conditions of persistent pain, inducing the release of chemicals, including proinflammatory cytokines, which further sensitize the pain pathways. Furthermore, animal and human studies have presented evidence in support of a link between the activation of brain microglia and negative affect (NA), including stress and anxiety. For instance, rodents exposed to stressful conditions were shown to exhibit microglial activation in several regions of the brain (thalamus, hypothalamus, hippocampus, substantia nigra and central gray). Despite these observations, NA- or pain-related neuroimmune activation in the human brain has never been demonstrated in vivo. As chronic pain patients exhibit high prevalence (~40-50%) of mood disorders, we will test the hypothesis that patients with chronic low back pain (cLBP) demonstrate evidence of activated brain microglia, and that this phenomenon is at least partly related to NA. Since microglia actively contribute to the modification or elimination of synapses, we will also determine the influence of activated microglia on functional brain connectivity. We will compare microglial activation and patterns of functional brain connectivity between cLBP patients with a wide range of NA levels and low-NA healthy volunteers. Subjects will be scanned using simultaneous Magnetic Resonance/Positron Emission Tomography (MR-PET), a novel technology synergizing two leading imaging methodologies. PET scanning will use [11C]PBR28, a novel marker of microglial activation. MR data collected simultaneously to PET data will allow us to a) estimate functional brain connectivity during microglia activity measurement, as well as b) perform an MR-based motion correction of the PET data (a novel procedure that significantly improves the fidelity, sensitivity, and specificity of PET data). Recognizing the role of microglia in human pain and negative affect would likely have important clinical implications, including improved diagnosis and the identification of objective markers for a wide range of neurological and psychiatric disorders.
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0.906 |
2016 — 2020 |
Loggia, Marco Luciano |
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. |
In-Vivo Imaging of Spinal and Brain Glial Activation in Low Back Pain Patients @ Massachusetts General Hospital
In animal models of pain, microglia and astrocytes become `activated' and start releasing pro- inflammatory cytokines and other products that further sensitize pain pathways. Thus, it is generally believed that glial cells actively contribute to the pathophysiology of persistent pain. Despite hundreds of studies with laboratory models, it is currently unclear whether glial cells have a role in human pain. Recently, however, our group has demonstrated that patients with chronic low back pain (cLBP) have increased brain levels of the 18kDa translocator protein (TSPO). In addition, preliminary data collected from a different cohort of cLBP patients suggest an increase in spinal cord TSPO levels as well. As TSPO upregulation is a marker of glial activation, these observations support a role for glial activation in human chronic pain. With the current proposal, which builds logically on our prior observations, we will compare spinal and brain glial activation in healthy volunteers, and patients with subacute (i.e., pain duration between 1 and 3 months) and chronic (i.e., pain duration > 1 year) low back pain. Scans will be performed with integrated Positron Emission Tomography / Magnetic Resonance (PET/MR) imaging and [11C]PBR28, a second- generation radioligand for TSPO, with an excellent ratio of specific-to-nonspecific binding. By comparing [11C]PBR28 scans in cLBP patients of different clinical presentation (i.e., with radicular pain vs axial pain) we will test the hypothesis that glial activation in the primary somatosensory/motor cortices follows a somatotopic organization that mirrors the somatic distribution of the patients' symptoms. Moreover, we will perform cross- sectional comparisons between subacute and chronic low back pain, as well as longitudinal studies of subacute low back pain patients across time, to capture the transition to chronic pain, or the return to pain-free status. These investigations will allow us to assess the temporal evolution of glial activation in humans with pain disorders. A subset of sLBP patients will be re-scanned after a 2-week treatment with either minocycline (which was recently found to reduce sLBP) or placebo. While minocycline is a known glial inhibitor in animal models, the mechanisms underlying its effect on human pain are unknown. Finally, we will compare the baseline status of glial activation in subacute patients that have subsequently transitioned to chronic pain, or have healed. This comparison will allow us to test the hypothesis that glial activation can predict transition from subacute to chronic pain. While this project is purposely focused on a specific condition (low back pain), the identification of a role of glia in the development and maintenance of persistent pain and pain-related disability will have important practical implications for the management of a wide range of pain disorders.
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0.906 |
2016 — 2020 |
Loggia, Marco Luciano |
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. |
The Role of Brain Glial Activation in Knee Ostoarthritis @ Massachusetts General Hospital
? DESCRIPTION (provided by applicant): Knee osteoarthritis (KOA) is one of the most prevalent causes of pain and disability, and its incidence continues to increase as the elderly and obese populations grow. While most KOA patients report reduced pain and improved function after Total Knee Arthroplasty (TKA), approximately 20% of them continue to experience significant pain and disability even years post-TKA. The factors underlying inter-individual differences in susceptibility to post-TKA pain are largely unknown. In this project, we will measure levels of the translocator protein (TSPO), a protein upregulated in activated glia, in the brains of patients undergoing TKA and evaluate TSPO's role in post-TKA pain. TSPO functions to limit the magnitude of glia-mediated inflammatory responses, thereby promoting the return to pre-injury status and recovery from pain. Thus, interindividual differences in TSPO expression may explain why a small but substantial percentage of OA patients do not fully heal following TKA. We will perform brain scans in 110 KOA patients (pre-surgically, 1-to-2 weeks post-TKA and, in a subset of patients also 12 months post-TKA), and in 25 healthy volunteers (once). All patients will be also evaluated clinically 1 year post-TKA. Brain scans will be performed using integrated Positron Emission Tomography / Magnetic Resonance (PET/MR) imaging and the recently developed [11C]PBR28 radioligand, which binds to TSPO. MR data collected simultaneously to PET data will allow us to perform an MR-based motion correction of the PET data (a novel procedure that significantly improves the fidelity, sensitivity, and specificity of PT data). First, we will test the hypothesis that pre-surgically KOA patients will demonstrate higher [11C]PBR28 brain binding than healthy controls, which will be evidence of KOA-related glial activation. Then we will evaluate the hypothesis that TKA itself leads to an additional increase of [11C]PBR28 brain binding, which will be evidence of TKA-related glial activation. We also hypothesize that at 1-year post-TKA, [11C]PBR28 binding will still be elevated in patients still experiencing significant pain and disability, whereas it will be reduced to the levels of the contrl subjects in recovered patients. Finally, we will test the hypothesis that [11C]PBR28 binding pre- and peri-surgically will predict occurrence of long-term postsurgical pain 1 year after TKA. In particular, given the proposed anti-inflammatory and pain-protective role of TSPO, we will test the hypothesis that low pre-surgical / peri-surgical TSPO levels will predict higher likelihood of developing post-TKA pain. The identification of a role of glia and its modulation in the development and maintenance of persistent pain and pain-related disability following TKA will have important practical implications for the management of post-operative pain, and the development of tailored preventive interventions focused on glial modulation.
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0.906 |
2018 — 2021 |
Loggia, Marco Luciano |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Boosting Mind-Body Mechanisms For Mitigating Neuroinflammation in Migraine @ Massachusetts General Hospital
Project Summary/Abstract Migraine headaches represent the third most prevalent medical disorder on the planet, yet many sufferers are not satisfactorily treated, and 3% of them suffer chronification of their migraine every year. Cortical spreading depression and hyperexcitability of the brain have been demonstrated in migraine, and migraine pain has been related to neuroinflammation. In this project, we propose to use PET/MRI using a translocator protein marker (TSPO), as well as a measure of the infra-slow oscillatory activity to assess neuroinflammation in migraine. Then, we will examine the effect of a mind-body therapy on neuroinflammation. Our design will combine a top- down approach, namely mindfulness mediation, with a bottom-up approach, i.e. non-invasive transcutaneous vagus nerve stimulation, and examine the synergistic effect of these therapies on both microglial/astrocytic activation as measured with PET and on the fluctuation of low-frequency oscillatory activity. Our results will indicate whether a coupling of a top-down with a bottom-up therapeutic approach can have measurable effects on neuroinflammation in migraine, and indicate whether glial activation may be a therapeutic target for migraine.
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0.906 |
2018 — 2020 |
Loggia, Marco Luciano Ratai, Eva-Maria |
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. |
Imaging Neuroglial Mechanisms of Neuropathic Pain-Opioid Interaction in Hiv @ Massachusetts General Hospital
Abstract To date, ~1.1 million people in the United State and ~37 million people worldwide are infected with the human immunodeficiency virus (HIV). Of those infected with HIV, almost a third experience distal symmetric polyneuropathy often associated with neuropathic pain. While opioids are currently the cornerstone medication for treating severe pain in these patients, they can paradoxically lead to an increase in sensitivity to noxious stimuli (opioid-induced hyperalgesia) as well as an exacerbation of HIV-associated clinical pain. The precise mechanisms by which opioids interact with the viral infection to exacerbate neuropathic pain have yet to be fully elucidated, but likely involve the synergetic dysregulation of neuro-glial interactions, including glial activation and alterations in the excitation-inhibition balance of the brain. Despite the rapid accumulation of preclinical studies investigating these mechanisms, human evidence is currently lacking. To evaluate the role of neuro-glial dysregulation as a mechanism underlying HIV-opioids interaction, in humans, we will use advanced brain imaging technologies and quantitative sensory testing (QST). Specifically, integrated [11C]PBR28 Positron Emission Tomography / Magnetic Resonance (PET/MR) and high field (7T) proton magnetic resonance spectroscopy (1H MRS) will be used to evaluate brain levels of glial markers (18kDa translocator protein, TSPO, and myo-inositol, mI), neuronal / structural integrity markers (N-acetyl- aspartate, NAA and gray matter volume) as well as excitatory and inhibitory neurotransmission markers (glutamate and gamma-aminobutyric acid, GABA). QST techniques will assess pain threshold, suprathreshold sensitivity and temporal summation. Four cohorts will be enrolled in this trial: 1) HIV-positive patients without neuropathic pain, 2) HIV-positive patients with neuropathic pain not on opioid therapy, 3) HIV-positive patients with neuropathic pain on opioid therapy and 4) healthy, pain-free HIV- volunteers. Elucidating the mechanisms mediating the HIV-opioid interaction will have important practical implications for pain management, and toward the development of tailored interventions focused on glial modulation and neurotransmitter signaling.
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0.906 |
2019 |
Loggia, Marco Luciano Schaechter, Judith Diane |
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.) |
A Study of Neuroimmune Mechanisms of Poststroke Fatigue Using Integrated Pet/Mri @ Massachusetts General Hospital
Excessive fatigue in stroke survivors, referred to as poststroke fatigue, is a common and disabling problem. The cause of poststroke fatigue is unknown and there is no effective treatment. Several observations point to a role of brain inflammation in poststroke fatigue. Among these observations, experimental manipulations that cause brain inflammation result in fatigue. Stroke is also known to cause brain inflammation, initially in the area of brain damage, then spreading to distant brain regions that are physically connected to the stroke-damaged tissue by neural pathways. While inflammation has been observed in brain regions distant from the damaged tissue in chronic stroke patients, no study has tested whether this inflammation is linked to poststroke fatigue. The proposed project will test, for the first time, the overall hypothesis that brain inflammation and associated changes in brain connectivity play an important role in poststroke fatigue in chronic stroke patients. To test this hypothesis, we will enroll 24 patients who had a stroke 1-year earlier, have good motor, cognitive and mood outcomes, and do not have a comorbid condition that might be expected to cause fatigue. The selected patients will have a range of fatigue, from low to high. Brain imaging will be performed by an integrated Positron Emission Tomography / Magnetic Resonance Imaging (PET/MRI) scanner and [11C]PBR28, a high sensitivity and specificity marker of brain inflammation. Use of the integrated PET/MRI scanner will allow us to acquire PET and MRI data simultaneously, which shortens scan time for patients, and also allows us to implement advanced methods for using the MRI data to improve the quality of the [11C]PBR28 PET data. Our first aim will be to localize brain regions where increased [11C]PBR28 signal, meaning increased inflammation, is associated with greater fatigue severity in the chronic stroke patients. Our second aim will be to evaluate whether brain inflammation is associated with changes in brain connectivity. To address this aim, we will measure brain connectivity in two ways. One way will be to measure the strength of white matter connections, commonly referred to as structural connectivity, using high angular resolution diffusion MRI. The other way will be to measure the strength of correlated neural signaling, commonly referred to as functional connectivity, using resting-state functional MRI. Together, the [11C]PBR28 PET and multi-modality MRI data will allow us to identify inflammatory and brain connectivity changes linked to poststroke fatigue. This new information will lay the groundwork for developing an effective treatment for poststroke fatigue. More broadly, our findings would open the door to examining the functional impact of chronic brain inflammation in stroke patients, a condition long known to exist but largely ignored in the context of understanding and treating persistent poststroke deficits. Our findings would also provide insight to biological mechanisms of the fatigue that is common in many other neurological conditions.
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0.906 |
2021 |
Gilman, Jodi Loggia, Marco Luciano |
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. |
Evaluation of Cannabidiol For Reduction of Brain Neuroinflammation @ Massachusetts General Hospital
Millions of individuals in the United States suffer from chronic pain and co-morbid depression, conditions that are debilitating and complex to manage. A reason for the scarcity of safe and efficacious therapies for these conditions is our limited knowledge of viable targets. Preclinical models of pain have shown that microglia and astrocytes play a key role in the establishment and/or maintenance of pain and depressive behaviors. Additionally, patients with chronic low back pain (cLBP) demonstrate ?pain-related? and ?depression-related? elevated levels of the glial marker 18kDa translocator protein (TSPO), suggesting that pain and depressive symptoms may be mediated / maintained by neuroinflammatory mechanisms In this proposal, we will study whether cannabidiol (CBD), the primary centrally and peripherally active non-intoxicating compound in the cannabis plant, exerts anti-neuroinflammatory effects in patients with cLBP with mild-to-moderate depression. In animals, CBD induces analgesic and antidepressant effects, via a complex pharmacology that includes the stimulation of cannabinoid receptors and the inhibition of pro- inflammatory pathways in glial cells. These preclinical studies, and our observations linking neuroinflammation to pain and comorbid depressive symptoms in cLBP, indicate that CBD may reduce both pain- and depression- related neuroinflammation in cLBP patients. In addition to exerting possible anti-neuroinflammatory effects, studies in psychiatric patients suggest that CBD might normalize striatal hypofunction, an alteration that our group has also recently linked to depression in cLBP patients using functional magnetic resonance imaging (fMRI). Because of its purported effects as striatal physiology, we thus hypothesize that a secondary mechanism of action of CBD may be to reduce striatal dysfunction. We will conduct a randomized, double-blind, 2-arm mechanistic trial to assess the effects of CBD (n = 40) and placebo (n = 40) in patients with cLBP with mild-to-moderate depression, using integrated positron emission tomography / magnetic resonance imaging (PET/MRI) scans. The use of integrated PET/MRI will allow us to simultaneously evaluate neuroinflammation (using [11C]PBR28, a second-generation radioligand for TSPO) and striatal function (using the Monetary Incentive Delay task, a validated fMRI task that probes behavioral and neural responses to rewards and losses). In our mechanistic trial, we will use EPIDIOLEX®, an FDA-approved product that contains a known and constant dose of purified CBD. We already hold an active IND to test the effects of EPIDIOLEX® in cLBP with [11C]PBR28 PET/MRI, and preliminary data support our hypotheses. By studying the neural and neuroimmune responses to CBD, this study will advance our knowledge about the mechanisms of action of this drug, and help us understand which conditions might benefit the most from its use. More broadly, our study will test whether modulating neuroinflammation is feasible and a promising therapeutic approach for pain and depression.
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0.906 |