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.

Public Health Relevance

Animal studies suggest that both exposure to stressful conditions, as well as persistent pain, lead to the activation of brain microglia -the principal innate immune cells of the central nervous system. As chronic pain patients exhibit high prevalence of mood disorders, we will use integrated MR-PET imaging to investigate whether brain microglia are also involved in pain and negative affect, as well as alterations in brain physiology, in chronic low back pain patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS087472-01A1
Application #
8823227
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Oshinsky, Michael L
Project Start
2014-09-15
Project End
2016-08-31
Budget Start
2014-09-15
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$261,000
Indirect Cost
$111,000
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199