An NIH-funded PET/MRI study of glial activation in the spinal cord and brain of people with low back pain. It examines differences between subacute and chronic pain and whether neuroinflammation relates to the transition to persistent symptoms.
Project abstract
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 unclea…Read the full abstractCollapse abstract
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.
Research connections
Publications
2025
Frontiers in neuroinformatics
INTRODUCTION: Neuroinflammation, a pathophysiological process involved in numerous disorders, is typically imaged using [11C]PBR28 (or TSPO) PET. However, this technique is limited by high costs and ionizing radiation, restricting its widespread clinical use. MRI, a more accessible alternative, is commonly used for structural or functional imaging, but when…Read the full abstractCollapse abstract
INTRODUCTION: Neuroinflammation, a pathophysiological process involved in numerous disorders, is typically imaged using [11C]PBR28 (or TSPO) PET. However, this technique is limited by high costs and ionizing radiation, restricting its widespread clinical use. MRI, a more accessible alternative, is commonly used for structural or functional imaging, but when used using traditional approaches has limited sensitivity to specific molecular processes. This study aims to develop a deep learning model to generate TSPO PET images from structural MRI data collected in human subjects.
METHODS: A total of 204 scans, from participants with knee osteoarthritis (n = 15 scanned once, 15 scanned twice, 14 scanned three times), back pain (n = 40 scanned twice, 3 scanned three times), and healthy controls (n = 28, scanned once), underwent simultaneous 3 T MRI and [11C]PBR28 TSPO PET scans. A 3D U-Net model was trained on 80% of these PET-MRI pairs and validated using 5-fold cross-validation. The model's accuracy in reconstructed PET from MRI only was assessed using various intensity and noise metrics.
RESULTS: The model achieved a low voxel-wise mean squared error (0.0033 ± 0.0010) across all folds and a median contrast-to-noise ratio of 0.0640 ± 0.2500 when comparing true to reconstructed PET images. The synthesized PET images accurately replicated the spatial patterns observed in the original PET data. Additionally, the reconstruction accuracy was maintained even after spatial normalization.
DISCUSSION: This study demonstrates that deep learning can accurately synthesize TSPO PET images from conventional, T1-weighted MRI. This approach could enable low-cost, noninvasive neuroinflammation imaging, expanding the clinical applicability of this imaging method.
2025
Brain, behavior, and immunity
Recent evidence suggests that chronic pain patients exhibit elevated brain levels of the neuroinflammation marker 18 kDa translocator protein (TSPO). However, the clinical significance of brain TSPO elevations, and their responses to pain interventions, remain unknown. To explore these questions, we studied patients with knee osteoarthritis (KOA) undergoing…Read the full abstractCollapse abstract
Recent evidence suggests that chronic pain patients exhibit elevated brain levels of the neuroinflammation marker 18 kDa translocator protein (TSPO). However, the clinical significance of brain TSPO elevations, and their responses to pain interventions, remain unknown. To explore these questions, we studied patients with knee osteoarthritis (KOA) undergoing total knee arthroplasty (TKA), a procedure which is curative for most, but carries a relatively high risk of persistent post-surgical pain. Pre-surgical KOA patients (n = 41) and healthy controls (n = 22) underwent brain positron emission tomography/magnetic resonance imaging, using the TSPO radioligand [11C]PBR28. A subset of KOA patients (n = 27) returned for a second scan one-year post-TKA. When compared groups, pre-surgical KOA patients exhibited widespread [11C]PBR28 PET signal elevations (Standardized Uptake Value Ratio), with pituitary uptake positively correlating with knee pain severity (rho = 0.51; p = 0.003). A voxel-wise paired t-test revealed that while most brain regions showed no change post-surgery, the [11C]PBR28 PET signal significantly decreased in the thalamus and caudate, reaching control levels. Additionally, a Support Vector Machine model based on pre-surgical imaging, clinical, and demographic features, achieved a correlation of rho = 0.487 (p = 0.001) between the predicted and actual pain improvement. Top predictive features included [11C]PBR28 uptake in the pituitary gland, cuneal cortex, amygdala and other regions. This study suggests that neuroinflammation 1) is widespread in KOA and, in some regions, 2) is linked to pain severity, 3) undergoes normalization following TKA, and 4) can predict post-surgical TKA outcomes. Understanding the neuroinflammatory mechanisms in KOA and post-surgical pain may guide targeted interventions and improve patient outcomes.